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1

Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients.  

PubMed

The 9q Subtelomeric Deletion Syndrome (9qSTDS) is clinically characterized by mental retardation, childhood hypotonia, and facial dysmorphisms. Haploinsufficiency of the EHMT1 gene has been demonstrated to be responsible for its core phenotype. In a significant number of patients behavioral abnormalities like aggression, impulsivity, and chaotic behaviors are present as well as epileptic phenomena. Reports about the developmental, behavioral, and neuropsychiatric aspects of 9qSTDS are scarce and mostly limited to young patients only. In this report, the behavioral and neuropsychiatric characteristics of one male and one female middle-aged patient are described in whom the genetic diagnosis, interstitial and telomeric 9q deletion, respectively, was established recently. In both patients a remarkable sleep disturbance, characterized by frequent awakenings and daytime sleepiness, was present as well as a prominent apathy syndrome. The observed motor signs such as rigid flexure of the arms and finger stereotypies persisted over a period of many years and could therefore not be viewed as symptoms of catatonia. It is concluded that the proposed behavioral phenotype of 9qSTDS comprises at least an erratic sleep pattern and an enduring severe apathy. PMID:19642112

Verhoeven, Willem M A; Kleefstra, Tjitske; Egger, Jos I M

2010-03-01

2

Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome  

PubMed Central

Background: A new syndrome has been recognised following thorough analysis of patients with a terminal submicroscopic subtelomeric deletion of chromosome 9q. These have in common severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, thickened lower lip, carp mouth with macroglossia, and conotruncal heart defects. The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q–) is approximately 1.2 Mb and encompasses at least 14 genes. Objective: To characterise the breakpoints of a de novo balanced translocation t(X;9)(p11.23;q34.3) in a mentally retarded female patient with clinical features similar to the 9q– syndrome. Results: Sequence analysis of the break points showed that the translocation was fully balanced and only one gene on chromosome 9 was disrupted—Euchromatin Histone Methyl Transferase1 (Eu-HMTase1)—encoding a histone H3 lysine 9 methyltransferase (H3-K9 HMTase). This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome. This observation was further supported by the spatio-temporal expression of the gene. Using tissue in situ hybridisation studies in mouse embryos and adult brain, Eu-HMTase1 was shown to be expressed in the developing nervous system and in specific peripheral tissues. While expression is selectively downregulated in adult brain, substantial expression is retained in the olfactory bulb, anterior/ventral lateral ventricular wall, and hippocampus and weakly in the piriform cortex. Conclusions: The expression pattern of this gene suggests a role in the CNS development and function, which is in line with the severe mental retardation and behaviour problems in patients who lack one copy of the gene. PMID:15805155

Kleefstra, T; Smidt, M; Banning, M; Oudakker, A; Van Esch, H; de Brouwer, A P M; Nillesen, W; Sistermans, E; Hamel, B; de Bruijn, D; Fryns, J; Yntema, H; Brunner, H; de Vries, B B A; van Bokhoven, H

2005-01-01

3

Dental developmental abnormalities in a patient with subtelomeric 7q36 deletion syndrome may confirm a novel role for the SHH gene?  

PubMed Central

Studies in mice demonstrated that the Shh gene is crucial for normal development of both incisors and molars, causing a severe retardation in tooth growth, which leads to abnormal placement of the tooth in the jaw and disrupted tooth morphogenesis. In humans the SHH gene is located on chromosome 7q36. Defects in its protein or signaling pathway may cause holoprosencephaly spectrum, a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres and that can be manifested in microforms such as single maxillary central incisor. A novel role for this gene in the developing human primary dentition was recently demonstrated. We report a 12-year old boy with a de novo 7q36.1-qter deletion characterized by high-resolution karyotyping, oligonucleotide aCGH and FISH. His phenotype includes intellectual disability, non-verbal communication, hypospadia, partial sacral agenesis and absence of coccyx, which are distinctive features of the syndrome and mainly correlated with the MNX1, HTR5A and EN2 genes. No microforms of holoprosencephaly spectrum were observed; but the patient had diastema and dental developmental abnormalities, such as conical, asymmetric and tapered inferior central incisors. The dental anomalies are reported herein for the first time in subtelomeric 7q36 deletion syndrome and may confirm clinically a novel role for the SHH gene in dental development. PMID:25606385

Linhares, Natália D.; Svartman, Marta; Salgado, Mauro Ivan; Rodrigues, Tatiane C.; da Costa, Silvia S.; Rosenberg, Carla; Valadares, Eugênia R.

2013-01-01

4

Cognitive-behavioral features of Wolf-Hirschhorn syndrome and other subtelomeric microdeletions.  

PubMed

Wolf-Hirschhorn syndrome (WHS) is a complex congenital malformation produced by a loss of genomic material at the locus 4p16.3. In addition to its dysmorphic features, the deletion produces a range of intellectual disability (ID). Many clinical aspects of WHS are well-characterized; however, the cognitive-behavioral characteristics have been rarely examined in a systematic fashion. The purpose of our study was to examine the cognitive-behavioral features of WHS and to compare them to children with other subtelomeric deletions that also produce ID. We recruited 45 children with subtelomeric deletions and examined their cognitive-behavioral abilities using a neuropsychological assessment battery composed of standardized instruments. Nineteen children were diagnosed with WHS and 26 children with one of three other subtelomeric deletions-11q25 (Jacobsen syndrome), deletion 2q37, and inversion duplication deletion 8p21-23. We found children with WHS to be more severely impacted cognitively than children from any of the other groups. Their overall adaptive behavior was lower as well. However, children with WHS exhibit strengths in socialization skills comparable to the levels attained by the other groups we assessed. Importantly, the proportion of children with WHS with autism or autistic-like features is significantly lower than the rates of autism found in the other subtelomeric disorders we examined. PMID:20981770

Fisch, Gene S; Grossfeld, Paul; Falk, Rena; Battaglia, Agatino; Youngblom, Janey; Simensen, Richard

2010-11-15

5

Array-CGH and clinical characterization in a patient with subtelomeric 6p deletion without ocular dysgenesis.  

PubMed

Subtelomeric terminal 6p deletion has been recognized as a clinically identifiable syndrome including facial dysmorphism, malformation of the anterior eye chamber, hearing loss, heart defects, and developmental delay. Genotype-phenotype correlations of previously published patients have strongly suggested anterior eye segment anomalies as one of the major malformations of the syndrome if the critical 6p25 region contains the FOXC 1 gene. In addition, the presence in this region of one or more genes involved in hearing loss has been hypothesized. We report a patient with a 47,XYY karyotype and submicroscopic terminal 6p deletion. Further characterization of the deletion with array comparative genome hybridization also revealed a cryptic microduplication on chromosome 19. The patient showed dysmorphic features, neuromotor retardation, and profound language impairment, in absence of hearing loss and structural eye anomalies. As far as we know this is the first reported terminal 6p25.1 deletion case without eye dysgenesis precisely characterized by array-CGH. Our result suggests that the genes in this region may not be obvious candidates for hearing loss and demonstrate the need for further elucidation of the function of the genes involved in eye developmental processes. PMID:22105932

Piccione, Maria; Antona, R; Salzano, E; Cavani, S; Malacarne, M; Morreale Bubella, R; Pierluigi, M; Viaggi, C D; Corsello, Giovanni

2012-01-01

6

Growth patterns of patients with 1p36 deletion syndrome.  

PubMed

1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes. Obesity is frequently observed in patients with this syndrome. Thus, it is important to evaluate the growth status of an individual patient. For this purpose, we accumulated recorded growth data from 44 patients with this syndrome and investigated the growth patterns of patients. Most of the patients showed weight parameters within normal limits, whereas a few of these patients showed intrauterine growth delay and microcephaly. The length of the patients after birth was under the 50th centile in most patients. Many patients showed poor weight gain after birth, and only two female patients were overweight. These findings indicate two different phenotypes of the 1p36 deletion syndrome. The overweight patients with 1p36 deletion started excessive weight gain after two years of life. This characteristic of the patients with 1p36 deletion syndrome is similar to Prader-Willi syndrome. PMID:24750553

Sangu, Noriko; Shimojima, Keiko; Shimada, Shino; Ando, Tomohiro; Yamamoto, Toshiyuki

2014-05-01

7

Genotype-phenotype correlations to aid in the prognosis of individuals with uncommon 20q13.33 subtelomere deletions: a collaborative study on behalf of the 'association des Cytogénéticiens de langue Française'.  

PubMed

The identification of subtelomeric rearrangements as a cause of mental retardation has made a considerable contribution to diagnosing patients with mental retardation. It is remarkable that for certain subtelomeric regions, deletions have hardly ever been reported so far. All the laboratories from the 'Association des Cytogénéticiens de Langue Française' were surveyed for cases where an abnormality of the subtelomere FISH analysis had been ascertained. Among 1511 cases referred owing to unexplained mental retardation, 115 (7.6%) patients showed a clinically significant subtelomeric abnormality. We report the clinical features and the molecular cytogenetic delineation of isolated de novo deletions on 20q13.33 in two cases. Detailed mapping was performed by micro-array CGH in one patient and confirmed by FISH in the two patients. We compare our data with the only three patients reported in the literature. Both patients shared a deleted region of approximately 1.33 Mb including 40 genes, with a 324 kb difference between the two patients. Haploinsufficiency for CHRNA4 and ARFGAP1 may have contributed towards a severe phenotype. In addition, the data in all patients suggest that haploinsufficiency for SOX18 may not cause the hypotrichosis-lymphedema-telangiectasia syndrome, or causes milder disease. Our study gives important information by defining the size of imbalance and better predicting the phenotype. Two clinically distinct phenotypes may be drawn, a mild mental retardation or a more complex and severe phenotype, according to the presence or absence of the CHRNA4 and ARFGAP1 genes respectively. PMID:17290276

Béri-Deixheimer, Mylène; Gregoire, Marie-José; Toutain, Annick; Brochet, Karène; Briault, Sylvain; Schaff, Jean-Luc; Leheup, Bruno; Jonveaux, Philippe

2007-04-01

8

Analysis of myelodysplastic syndromes with complex karyotypes by high-resolution comparative genomic hybridization and subtelomeric CGH array.  

PubMed

Molecular cytogenetic techniques enabled us to clarify numerical and structural alterations previously detected by conventional cytogenetic techniques in 37 patients who had myelodysplastic syndromes with complex karyotypes. Using high-resolution comparative genomic hybridization (HR-CGH), we found the most recurrent alterations to be deletion of 5q (70%), 18q (35%), 7q (32%), 11q (30%), and 20q (24%), gain of 11q (35%) and 8q (24%), and trisomy of chromosome 8 (19%). Furthermore, in 35% of the patients, 20 amplifications were identified. These amplifications were shown by FISH to involve some genes previously described as amplified in hematological malignancies, such as ERBB2, MLL, and RUNX1. In addition, two other genes, BCL6 and BCL2, which are classically related to apoptosis and non-Hodgkin lymphoma, were shown for the first time to be involved in amplification. Genomic alterations involving different subtelomeric regions with losses in 4p16, 5p15.3, 6q27, 18p11.3, and 18q23 and gains in 1p36.3 and 19p13.3 were detected by HR-CGH. Array CGH analysis of the subtelomeric regions in some samples was able to confirm a number of these alterations and found some additional alterations not detected by conventional CGH. PMID:15611930

Martínez-Ramírez, Angel; Urioste, Miguel; Melchor, Lorenzo; Blesa, David; Valle, Laura; de Andrés, Sara Alvarez; Kok, Klaas; Calasanz, Maria José; Cigudosa, Juan Cruz; Benítez, Javier

2005-03-01

9

Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements.  

PubMed

Chromosome rearrangements are a significant cause of intellectual disability and birth defects. Subtelomeric rearrangements, including deletions, duplications and translocations of chromosome ends, were first discovered over 40 years ago and are now recognized as being responsible for several genetic syndromes. Unlike the deletions and duplications that cause some genomic disorders, subtelomeric rearrangements do not typically have recurrent breakpoints and involve many different chromosome ends. To capture the molecular mechanisms responsible for this heterogeneous class of chromosome abnormality, we coupled high-resolution array CGH with breakpoint junction sequencing of a diverse collection of subtelomeric rearrangements. We analyzed 102 breakpoints corresponding to 78 rearrangements involving 28 chromosome ends. Sequencing 21 breakpoint junctions revealed signatures of non-homologous end-joining, non-allelic homologous recombination between interspersed repeats and DNA replication processes. Thus, subtelomeric rearrangements arise from diverse mutational mechanisms. In addition, we find hotspots of subtelomeric breakage at the end of chromosomes 9q and 22q; these sites may correspond to genomic regions that are particularly susceptible to double-strand breaks. Finally, fine-mapping the smallest subtelomeric rearrangements has narrowed the critical regions for some chromosomal disorders. PMID:21729882

Luo, Yue; Hermetz, Karen E; Jackson, Jodi M; Mulle, Jennifer G; Dodd, Anne; Tsuchiya, Karen D; Ballif, Blake C; Shaffer, Lisa G; Cody, Jannine D; Ledbetter, David H; Martin, Christa L; Rudd, M Katharine

2011-10-01

10

Two further AHO-like syndrome patients with deletion of glypican 1 gene region in 2q37.2-q37.3.  

PubMed

In this report, we describe two unrelated patients with mental retardation and brachydactyly E classified as patients suffering from Albright hereditary osteodystrophy-like (AHO-like) syndrome. Fluorescence in situ hybridization (FISH) analysis using 8 different subtelomeric probes in 2q36-37 proved that the patients had subtelomeric 2qter deletions of similar size. The recently proposed candidate gene glypican 1 (GPC1) is deleted in both reported patients. PMID:15547662

Polityko, Anna; Maltseva, Olga; Rumyantseva, Natalia; Khurs, Olga; Seidel, Jörg; Claussen, Uwe; Weise, Anja; Liehr, Thomas; Starke, Heike

2004-12-01

11

De novo Subtelomeric Deletion Additional to an Inherited Apparently Balanced Reciprocal Translocation  

Microsoft Academic Search

Objective: We describe the analysis of an apparently balanced inherited reciprocal translocation in a fetus presenting with multiple congenital abnormalities, characterize the structural chromosome rearrangement, and report an unexpected additional imbalance to the inherited rearrangement. Methods: DNA microarray was used to screen for genomic imbalance in subtelomeric and interstitial critical regions. High-resolution comparative genomic hybridization was used to screen for

A. Delahaye; E. Pipiras; S. Kanafani; C. Touboul; A. Vergnaud; F. Encha-Razavi; M. Sinico; M. Benkhalifa; S. Kasakyan; S. Serero; J. P. Wolf; M. Gérard-Blanluet; B. Benzacken

2007-01-01

12

Array-CGH analysis and clinical description of 2q37.3 de novo subtelomeric deletion.  

PubMed

We report on a 13-year-old girl with normal karyotype and a de novo cryptic terminal deletion of chromosome 2q, detected by subtelomeric FISH analysis. Further investigation with array-CGH analysis using the 1Mb resolution Spectral Chip 2600 (Spectral Genomics) confirmed the deletion and also showed a deletion of four additional clones. No other abnormalities were detected by array-CGH. FISH studies using 8 BAC-probes were performed for fine mapping of the deletion and confirmed the array results. FISH analysis showed that the deletion breakpoint lies between clones RP11-84G18 and RP11-83N2 (physical distance between clones 0.36Mb) and extends to the telomere. The size of the deletion was estimated to be about 6.4-6.7Mb. Clinical findings include: developmental delay, severe behavioural disturbances, growth-pubertal retardation, congenital conductive mild hearing loss, growth hormone deficiency, compensate hypothyroidism, dysmorphic facial features, excessive joint hypermobility, brachymetaphalangy, abnormal dermatoglyphics and a history of neonatal laryngomalacia, hypotonia and umbilical hernia. The phenotype of our patient is in keeping with those of the literature, with the exception of cardiovascular, urogenital, neurological anomalies and eczema, which were not observed. The report of the clinical and molecular presentation of similar cases will allow accurate phenotype-genotype correlation and proper genetic counseling of the family. PMID:17194633

Kitsiou-Tzeli, Sofia; Sismani, Carolina; Ioannides, Marios; Bashiardes, Stavros; Ketoni, Andria; Touliatou, Vassiliki; Kolialexi, Aggeliki; Mavrou, Ariadni; Kanavakis, Emanuel; Patsalis, Philippos C

2007-01-01

13

Subtelomeric Deletion of Chromosome 10p15.3: Clinical Findings and Molecular Cytogenetic Characterization  

PubMed Central

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11,), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM# 608668) and DIP2C (OMIM# 611380) (UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study. PMID:22847950

DeScipio, Cheryl; Conlin, Laura; Rosenfeld, Jill; Tepperberg, James; Pasion, Romela; Patel, Ankita; McDonald, Marie T; Aradhya, Swaroop; Ho, Darlene; Goldstein, Jennifer; McGuire, Marianne; Mulchandani, Surabhi; Medne, Livija; Rupps, Rosemarie; Serrano, Alvaro H.; Thorland, Erik C; Tsai, Anne C-H; Hilhorst-Hofstee, Yvonne; Ruivenkamp, Claudia AL; Van Esch, Hilde; Addor, Marie-Claude; Martinet, Danielle; Mason, Thornton B.A.; Clark, Dinah; Spinner, Nancy B; Krantz, Ian D

2012-01-01

14

A case of an atypically large proximal 15q deletion as cause for Prader-Willi syndrome arising from a de novo unbalanced translocation.  

PubMed

We describe an 11 month old female with Prader-Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype. PMID:23856564

Hickey, Scott E; Thrush, Devon Lamb; Walters-Sen, Lauren; Reshmi, Shalini C; Astbury, Caroline; Gastier-Foster, Julie M; Atkin, Joan

2013-09-01

15

Cognitive-behavioral characteristics and developmental trajectories in children with deletion 11qter (Jacobsen syndrome), and their relation to deletion size.  

PubMed

Subtelomeric deletions represent an important class of abnormalities to be considered when investigating genetic links to intellectual disability (ID). One subtelomeric deletion found on the long arm of chromosome 11q produces a characteristic phenotype that includes ID and is often referred to as Jacobsen syndrome (JBS). Previously, researchers found an inverse relationship between IQ and deletion size. While useful, IQ does not provide a comprehensive picture of the cognitive-behavioral strengths and weaknesses in JBS, nor does it reveal how the profiles evolve as these individuals age. One purpose of this study was to confirm the relationship between IQ or adaptive behavior (DQ) and deletion size. We also examined cognitive-behavioral profiles of children with JBS and the extent to which they changed over time. Initially, at T1, we examined 10 children, ages 5-20 years, diagnosed with JBS. Cognitive ability was assessed with the Stanford-Binet (4th Edition). Adaptive behavoir was evaluated with the Vineland Adaptive Behavior Scales (VABS). Eight children were reassessed 2 years later (T2). Results show a negative but non-significant correlation between IQ and deletion size. There was no statistically significant relationship between DQ and deletion size. As for our second aim, IQ and DQ scores were stable from T1 to T2. Cognitive profiles were not significantly different from T1 to T2. However, there were significant changes in adaptive behavior domain scores from T1 to T2. Lack of a significant relationship between cognitive-behavioral measures and deletion size, as well as changes in cognitive-behavioral profiles are discussed. © 2014 Wiley Periodicals, Inc. PMID:25425441

Fisch, Gene S

2015-01-01

16

Genetics Home Reference: 22q13.3 deletion syndrome  

MedlinePLUS

... 3 deletion syndrome are known. What are the genetic changes related to 22q13.3 deletion syndrome? 22q13. ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

17

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist  

Microsoft Academic Search

BACKGROUNDSubmicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.METHODSWe studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital

B B A de Vries; S M White; S J L Knight; R Regan; T Homfray; I D Young; M Super; C McKeown; M Splitt; O W J Quarrell; A H Trainer; M F Niermeijer; S Malcolm; J Flint; J A Hurst; R M Winter

2001-01-01

18

Genetics Home Reference: 1p36 deletion syndrome  

MedlinePLUS

... individuals are likely never diagnosed. What are the genetic changes related to 1p36 deletion syndrome? 1p36 deletion ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

19

Genetics Home Reference: 22q11.2 deletion syndrome  

MedlinePLUS

... affect almost any part of the body. The features of this syndrome vary widely, even among affected ... the mouth (a cleft palate), and distinctive facial features. People with 22q11.2 deletion syndrome often experience ...

20

Dermatoglyphic Profile in 22q Deletion Syndrome  

PubMed Central

A genetic subtype of schizophrenia has been described in 22q11 Deletion syndrome. Previous studies have described an excess of dermatoglyphic alterations in schizophrenia, such as low a–b ridge counts (ABRCs), a high frequency of ridge dissociations, and increased dermatoglyphic fluctuating asymmetry. Little is known however, about the dermatoglyphic profile of 22qDS subjects showing psychotic symptoms and its similarity to the previously reported anomalies in schizophrenia. We studied the palmar dermatoglyphics of 22 subjects with 22qDS of predominantly Caucasian origin, 15 of whom had psychotic illness, and in 84 healthy controls of similar ethnicity. We observed higher values for total ATD angle in cases than in controls (P = 0.04). In addition, there was an excess of radial figures in the hypothenar area in cases, especially in the left hand. Interestingly, greater fluctuating asymmetry, determined by the absolute difference between right and left ABRC, was observed in 22qDS subjects compared to controls (P = 0.05). However, no differences were found for ABRCs and frequency of dissociations. Despite the small sample size, the palmprints analyzed suggest the existence of an altered dermatoglyphic profile in 22qDS, involving: (i) ATD angle amplitude, (ii) presence of radial loops in the hypothenar area, and (iii) an increment of fluctuating asymmetry. The first two features are similar to those found in other genetic syndromes associated with low IQ, while high levels of fluctuating asymmetry have often been reported in schizophrenia. PMID:15211630

Martín, B.; Fañanás, L.; Gutiérrez, B.; Chow, E.W.C.; Bassett, A.S.

2011-01-01

21

Genetics Home Reference: 16p11.2 deletion syndrome  

MedlinePLUS

... Most also have at least some features of autism spectrum disorders. These disorders are characterized by impaired ... Registry: 16p11.2 deletion syndrome Genetic Testing Registry: Autism, susceptibility to, 14a You might also find information ...

22

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.  

PubMed

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8?Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1. PMID:23073310

Leroy, Camille; Landais, Emilie; Briault, Sylvain; David, Albert; Tassy, Olivier; Gruchy, Nicolas; Delobel, Bruno; Grégoire, Marie-José; Leheup, Bruno; Taine, Laurence; Lacombe, Didier; Delrue, Marie-Ange; Toutain, Annick; Paubel, Agathe; Mugneret, Francine; Thauvin-Robinet, Christel; Arpin, Stéphanie; Le Caignec, Cedric; Jonveaux, Philippe; Beri, Mylène; Leporrier, Nathalie; Motte, Jacques; Fiquet, Caroline; Brichet, Olivier; Mozelle-Nivoix, Monique; Sabouraud, Pascal; Golovkine, Nathalie; Bednarek, Nathalie; Gaillard, Dominique; Doco-Fenzy, Martine

2013-06-01

23

Genetics Home Reference: 2q37 deletion syndrome  

MedlinePLUS

... 2q37 deletion syndrome have a rare form of kidney cancer called Wilms tumor. Some affected individuals have malformations of the brain, ... disability ; eczema ; gastrointestinal ; genitalia ; hereditary ; hypotonia ; inherit ; ... syndrome ; translocation ; tumor ; Wilms tumor You may find definitions for these ...

24

Features of Two Cases with 18q Deletion Syndrome  

PubMed Central

The 18q Deletion syndrome is seen in 1 out of 10 000 live births. The main features of the syndrome are short stature, hearing loss, hypotonia, mental retardation, endocrine disorders and autoimmunity. Here, we present 2 patients with this syndrome admitted to our clinic who were found to have insulin resistance in addition to mental retardation, short stature, autoimmune thyroiditis and hearing loss. The need to perform a karyogram analysis in cases presenting with these features is emphasized. PMID:24637311

Özsu, Elif; Ye?iltepe Mutlu, Gül; Büte Yüksel, Ay?egül; Hatun, ?ükrü

2014-01-01

25

Features of two cases with 18q deletion syndrome.  

PubMed

The 18q Deletion syndrome is seen in 1 out of 10 000 live births. The main features of the syndrome are short stature, hearing loss, hypotonia, mental retardation, endocrine disorders and autoimmunity. Here, we present 2 patients with this syndrome admitted to our clinic who were found to have insulin resistance in addition to mental retardation, short stature, autoimmune thyroiditis and hearing loss. The need to perform a karyogram analysis in cases presenting with these features is emphasized. PMID:24637311

Özsu, Elif; Mutlu, Gül Ye?iltepe; Yüksel, Ay?egül Bütel; Hatun, ?ükrü

2014-01-01

26

Deletions of the elastin gene in Williams Syndrome  

SciTech Connect

To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

Greenberg, F.; Nickerson, E.; McCaskill, C. [Baylor College of Medicine, Houston, TX (United States)] [and others

1994-09-01

27

18q deletion syndrome – A case report  

PubMed Central

ABSTRACT We report on a 3 years old boy with severe mental retardation, hypotonia, deafness, cerebral dysmyelination, low levels of immunoglobulin A and dysmorphic features, bearing a distal deletion of 18q: 18q21-qter. Karyotype analysis by GTG banding was performed, revealing a deletion of the distal fragment of chromosome 18q, ranging from band q21 to qter, later confirmed by Fluorescence In Situ Hybridization (FISH). Whole chromosome painting for chromosome 18 ruled out any cryptic rearrangements involving other chromosomes. An attempted therapy with growth hormone did not bring any improvement and was discontinued due to an unexplained febrile episode and overall regress of the patient. PMID:21977138

BUDISTEANU, Magdalena; ARGHIR, Aurora; CHIRIEAC, Sorina Mihaela; TUTULAN-CUNITA, Andreea; LUNGEANU, Agripina

2010-01-01

28

Narrowing the candidate region of Albright hereditary osteodystrophy-like syndrome by deletion mapping in a patient with an unbalanced cryptic translocation t(2;6)(q37.3;q26).  

PubMed

We here describe a submicroscopic translocation affecting the subtelomeric regions of chromosomes 2q and 6q identified in a patient referred to us because of mental retardation, obesity, brachydactyly, and short stature. FISH analysis using subtelomeric probes showed a 46,XY,der(2)t(2;6)(q37.3;q26) in the propositus, and a balanced t(2;6) in his father and sister. FISH with region-specific genomic clones made it possible to map the 2q37.3 breakpoint precisely to the region covered by BAC 585E12, and the 6q26 breakpoint to between the regions encompassed by 414A5 and 480A20. The 2q subtelomeric deletion has often been found in patients with Albright hereditary osteodystrophy (AHO)-like syndrome but, to the best of our knowledge, the 2q37.3-qter monosomy ascertained in our patient is the smallest so far described within the syndrome's critical interval, and may thus enhance the search for the responsible genes. PMID:12966529

Giardino, Daniela; Finelli, Palma; Gottardi, Giulietta; De Canal, Gabriella; Della Monica, Matteo; Lonardo, Fortunato; Scarano, Gioacchino; Larizza, Lidia

2003-10-15

29

Delineation of 14q32.3 deletion syndrome.  

PubMed Central

A patient with a 14q32.3 terminal band deletion and cat cry is reported. Review of four other 14q32.3 deletion cases suggests the possible presence of a recognisable 14q32.3 terminal deletion syndrome, which is characterised by (1) apparently postnatal onset of small head size in comparison to body size, (2) high forehead with lateral hypertrichosis, (3) epicanthic folds, (4) broad nasal bridge, (5) high arched palate, (6) single palmar crease, and (7) mild to moderate developmental delay. Although none of the above seven features in unique to this syndrome, and indeed are quite common in other chromosomal disorders or genetic syndromes, patients with a terminal 14q32.3 deletion do show a recognisable facial gestalt. Interestingly, unlike ring chromosome 14, the 14q32.3 terminal deletion has rarely been reported, possibly because it is harder to detect, and an optimal chromosome preparation is required for its identification. Images PMID:9192277

Ortigas, A P; Stein, C K; Thomson, L L; Hoo, J J

1997-01-01

30

Further delineation of the 22q13 deletion syndrome.  

PubMed

A chromosomal deletion syndrome associated with a 22q13 microdeletion has previously been reported in approximately 75 children. We report six cases from Denmark with a deletion of 22q13. One was cytogenetically visible by conventional karyotyping, one was diagnosed by high resolution karyotyping after the demonstration of low arylsulfatase A activity. Two were diagnosed by high resolution CGH analysis, one was diagnosed by multisubtelomeric FISH analysis and one was diagnosed serendipitously as lack of the control signal in a FISH analysis for 22q11 deletion. One of the cases was a mosaic with 16% of cells showing two signals. The phenotype of the children included: generalized developmental delay, compromised language development, hypotonia, normal or accelerated growth and minor facial dysmorphism. Other features were partial agenesis of the corpus callosum, bilateral ureteropelvic stricture, gastroesophageal reflux and hearing loss. One case had a different phenotype, and showed a deletion as well as a duplication. The extent of the deletion was studied by quantitative PCR analysis of a number of DNA markers in the 22q13 region. The deletions varied in size, extending from 4.0 to 9.0 Mb. The clinical phenotype seemed rather similar although some specific features might be attributable to differences in deletions. PMID:15770125

Lindquist, S G; Kirchhoff, M; Lundsteen, C; Pedersen, W; Erichsen, G; Kristensen, K; Lillquist, K; Smedegaard, H H; Skov, L; Tommerup, N; Brøndum-Nielsen, K

2005-04-01

31

Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region  

SciTech Connect

Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and The D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. 28 refs., 6 figs.

Michaelis, R.C.; Skinner, S.A.; Lethco, B.A. [Greenwood Genetic Center, SC (United States)] [and others

1995-01-02

32

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA  

Microsoft Academic Search

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have

Michela Barbaro; Antonio Balsamo; Britt Marie Anderlid; Anne Grethe Myhre; Monia Gennari; Annalisa Nicoletti; Maria Carla Pittalis; Mikael Oscarson; Anna Wedell

2009-01-01

33

Cardiac Defects and Results of Cardiac Surgery in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

Specific types and subtypes of cardiac defects have been described in children with 22q11.2 deletion syndrome as well as in other genetic syndromes. The conotruncal heart defects occurring in patients with 22q11.2 deletion syndrome include tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus, interrupted aortic…

Carotti, Adriano; Digilio, Maria Cristina; Piacentini, Gerardo; Saffirio, Claudia; Di Donato, Roberto M.; Marino, Bruno

2008-01-01

34

Hematological abnormalities and 22q11.2 deletion syndrome.  

PubMed

The 22q11.2 deletion syndrome (22q11DS) is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test) were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene) and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome. PMID:23284264

Rosa, Rafael Fabiano Machado; Rosa, Rosana Cardoso Manique; Dos Santos, Pedro Paulo Albino; Zen, Paulo Ricardo Gazzola; Paskulin, Giorgio Adriano

2011-01-01

35

Type II diabetes and impaired glucose tolerance due to severe hyperinsulinism in patients with 1p36 deletion syndrome and a Prader-Willi-like phenotype  

PubMed Central

Background Deletion of the subtelomeric region of 1p36 is one of the most common subtelomeric deletion syndromes. In monosomy 1p36, the presence of obesity is poorly defined, and glucose metabolism deficiency is rarely reported. However, the presence of a typical Prader-Willi-like phenotype in patients with monosomy 1p36 is controversial. Case presentation In this report, we describe two female patients, one who is 6 years 2 months of age and another who is 10 years 1 month of age, both referred to our hospital for obesity and a Prader-Willi-like phenotype. These patients presented with severe obesity (body mass index [BMI] was 26.4 and 27.7, respectively), hyperphagia and developmental delay. Analysis of basal hormone levels showed normal thyroid function and adrenal function but considerable basal hyperinsulinism (the insulin levels were 54.5 and 49.2 ?U/ml, respectively). In patient 1, glycaemia was 75 mg/dl (HOMA-R 10.09), and the HbA1c level was 6.1%; in patient 2, glycaemia was 122 mg/dl, and the HbA1c level was 6.6% (HOMA-R 14.82). An oral glucose tolerance test demonstrated impaired glucose tolerance and diabetes mellitus with marked insulin resistance (the peak insulin level for each patient was 197 and 279 ?U/mL, respectively, while the 120’ insulin level of each patient was 167 and 234 ?U/mL, respectively). Conclusion some patients with monosomy 1p36 may show Prader-Willi-like physical and physiologic characteristics such as obesity and hyperinsulinism with impaired glucose metabolism, which can cause type II diabetes mellitus. Further studies are necessary to evaluate these findings. PMID:24479866

2014-01-01

36

Duplication and Deletion of CFC1 Associated with Heterotaxy Syndrome.  

PubMed

Heterotaxy syndrome, which causes significant morbidity and mortality, is a class of congenital disorders, in which normal left-right asymmetry cannot be properly established. To explore the role of copy number variants (CNVs) in the occurrence of heterotaxy syndrome, we recruited 93 heterotaxy patients and studied 12 of them by the Affymetrix Genome-Wide Human SNP 6.0 Array. The results were confirmed in the remaining 81 patients and 500 healthy children by quantitative real-time polymerase chain reaction (qPCR). The analysis of the SNP6.0 array showed a duplication of chromosome 2q21.1, which was verified by qPCR. The result of qPCR in the other 81 patients showed that 8/81 patients had the CNVs of 2q21.1 and the only overlapping gene in these patients is CFC1. However, in the 500 healthy children, only one carried the duplication of CFC1 (p=3.5×10(-7)). The duplication and deletion of CFC1 may play key roles in the occurrence of heterotaxy syndrome. Moreover, the transposed great arteries, double outlet right ventricle, single atrium, and single ventricle may share a common genetic etiology with the heterotaxy syndrome. PMID:25423076

Cao, Ruixue; Long, Fei; Wang, Liping; Xu, Yuejuan; Guo, Ying; Li, Fen; Chen, Sun; Sun, Kun; Xu, Rang

2014-11-25

37

Chromosome 9p deletion syndrome and sex reversal: novel findings and redefinition of the critically deleted regions.  

PubMed

Deletions of the short arm of chromosome 9 are associated with two distinct clinical entities. Small telomeric 9p24.3 deletions cause genital anomalies in male subjects, ranging from disorder of gonadal sex to genital differentiation anomalies, while large terminal or interstitial deletions result in 9p-malformation syndrome phenotype. The critical region for non-syndromic 46,XY sex reversal was assigned to a 1?Mb interval of chromosome 9p, extending from the telomere to the DMRT genes cluster. The 9p-syndrome was assigned to bands 9p22.3p24.1, but a phenotypic map has not been established for this condition, probably because of the lack of detailed molecular and/or phenotypic characterization, as well as frequent involvement of additional chromosome rearrangements. Here, we describe a unique patient with a small isolated 9p terminal deletion, characterized by array-CGH and FISH, who shows a complex phenotype with multiple physical anomalies, resembling the 9p-syndrome, disorder of sex development with gonadoblastoma, congenital heart defect and epilepsy. The observed deletion includes the 46,XY sex-reversal critical region, excluding the region so far associated with the 9p-syndrome. Genotype-phenotype correlations are tentatively established comparing our patient to seven other previously reported males with isolated terminal 9p deletions, finely defined at a molecular level. Our observations expand the 9p deletion clinical spectrum, and add significantly to the definition of a 9p-syndrome critical region. PMID:22821627

Onesimo, Roberta; Orteschi, Daniela; Scalzone, Maria; Rossodivita, Aurora; Nanni, Lorenzo; Zannoni, Gian Franco; Marrocco, Giacinto; Battaglia, Domenica; Fundarò, Carlo; Neri, Giovanni

2012-09-01

38

Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome  

E-print Network

Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome Anne S. Bassett, MD Sullivan, MD, PhD, Ann Swillen, PhD, Jacob Vorstman, MD, PhD, and The International 22q11.2 Deletion Syndrome Consortium** A 12-year-old boy currently is followed by multiple sub- specialists for problems

Nguyen, Danh

39

Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity.  

PubMed

Subtelomeres consist of sequences adjacent to telomeres and contain genes involved in important cellular functions, as subtelomere instability is associated with several human diseases. Balancing between subtelomere stability and plasticity is particularly important for Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis. T. brucei regularly switches its major variant surface antigen, variant surface glycoprotein (VSG), to evade the host immune response, and VSGs are expressed exclusively from subtelomeres in a strictly monoallelic fashion. Telomere proteins are important for protecting chromosome ends from illegitimate DNA processes. However, whether they contribute to subtelomere integrity and stability has not been well studied. We have identified a novel T. brucei telomere protein, T. brucei TRF-Interacting Factor 2 (TbTIF2), as a functional homolog of mammalian TIN2. A transient depletion of TbTIF2 led to an elevated VSG switching frequency and an increased amount of DNA double-strand breaks (DSBs) in both active and silent subtelomeric bloodstream form expression sites (BESs). Therefore, TbTIF2 plays an important role in VSG switching regulation and is important for subtelomere integrity and stability. TbTIF2 depletion increased the association of TbRAD51 with the telomeric and subtelomeric chromatin, and TbRAD51 deletion further increased subtelomeric DSBs in TbTIF2-depleted cells, suggesting that TbRAD51-mediated DSB repair is the underlying mechanism of subsequent VSG switching. Surprisingly, significantly more TbRAD51 associated with the active BES than with the silent BESs upon TbTIF2 depletion, and TbRAD51 deletion induced much more DSBs in the active BES than in the silent BESs in TbTIF2-depleted cells, suggesting that TbRAD51 preferentially repairs DSBs in the active BES. PMID:24810301

Jehi, Sanaa E; Wu, Fan; Li, Bibo

2014-07-01

40

Keratoconus in an adult with 22q11.2 deletion syndrome.  

PubMed

22q11.2 Deletion syndrome is one of the most common microdeletional syndromes, with an incidence of 1:4000 live-births, and potentially affects every organ in the body. More than 180 associated clinical features have been reported and not one phenotypic feature is present in 100% of cases. Ocular manifestations reported based on early childhood examinations include eyelid hooding, strabismus, posterior embryotoxon, retinal vessel tortuosity and refractive errors. Keratoconus has been reported once before in association with 22q11.2 deletion syndrome in a young adult. We report the second case of keratoconus in association with 22q11.2 deletion syndrome. PMID:25596286

Saffra, Norman; Reinherz, Benjamin

2015-01-01

41

Molecular characterization of a cryptic 2q37 deletion in a patient with Albright hereditary osteodystrophy-like phenotype.  

PubMed

The Albright hereditary osteodystrophy-like (AHO-like) syndrome was recently defined as a rare dysmorphic syndrome including brachymetaphalangism and mental retardation. This phenotype occurs in Albright hereditary osteodystrophy (AHO) but unlike it, the level of the Gs alpha protein activity is not reduced. To date 59 patients with these clinical and biochemical features have been reported, and for the majority of them (57/59) a cytogenetically visible 2q37 deletion has been observed. We report a new case of typical AHO-like syndrome with normal karyotype. Using the polymorphic marker D2S125 we found a loss of heterozygosity suggestive of a de novo 2q37 deletion of maternal origin. This hypothesis was confirmed by FISH analysis with a subtelomeric 2q probe containing the D2S90 marker. Genotypic analysis allowed us to map the proximal breakpoint of the subtelomeric deletion within an interval delimited by D2S2338 (present) and D2S2253 (deleted). This 2q subtelomeric deletion as small as 4 Mb is to date the smallest one observed in association with a typical AHO-like phenotype, and allows us to move the centromeric boundary of the AHO-like critical region by 750 kb towards the 2q telomere. PMID:15264288

Chassaing, N; De Mas, P; Tauber, M; Vincent, M C; Julia, S; Bourrouillou, G; Calvas, P; Bieth, E

2004-08-01

42

Syndrome of proximal interstitial deletion 4p15  

SciTech Connect

In this journal, Chitayat et al. reported on 2 boys and a girl with interstitial deletion in the short arm of chromosome 4, including p15.2p15.33. All 3 patients had a characteristic face distinct from that of Wolf-Hirschhorn syndrome and multiple minor congenital anomalies. One patient had a congenitally enlarged penis. The authors noted that all had normal growth, and all had moderate psychomotor retardation (patient 1, developmental age of 4-6 years at age 9 years; patient 2, mental age 6 years at age 25 years; and patient 3, global delay with hypotonia, difficulties in both gross and fine motor development, and persistent delay in language skills). 5 refs., 1 fig.

Fryns, J.P. [Univ. of Leuven (Belgium)

1995-09-11

43

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA.  

PubMed

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed. PMID:19417767

Barbaro, Michela; Balsamo, Antonio; Anderlid, Britt Marie; Myhre, Anne Grethe; Gennari, Monia; Nicoletti, Annalisa; Pittalis, Maria Carla; Oscarson, Mikael; Wedell, Anna

2009-11-01

44

[Clinical manifestation of chromosome 2 long arm terminal deletion--presentation of four cases].  

PubMed

Terminal deletion of the long arm of chromosome 2 belongs to the most common structural aberrations of subtelomeric chromosomal regions. Clinical manifestations of this syndrome comprise: global psychomotor delay, moderate to severe mental retardation with specific facial dysmorphism. In some cases a phenotype similar to Albright's hereditary osteodystrophy (AHO) may also be observed (short stature, obesity, brachydactyly). The paper covers the characteristics of clinical features in four cases of terminal deletions in 2q36.2, 2q37.1 and 2q37.3 identified in routine cytogenetic study and fluorescent in situ hybridization (FISH) technique. In one case the deletion of subtelomeric region of chromosome 2 (2q37.3) occurred as a result of reciprocal translocation between chromosomes 2 and 7. A comparison was made of clinical symptoms present in our patients with relevant data concerning other cases of 2q monosomy, described in specialized publications. PMID:17965466

Szcza?uba, Krzysztof; Obersztyn, Ewa; Ziemkiewicz, Kamila; Jamsheer, Aleksander; Bocian, Ewa; Mazurczak, Tadeusz

2007-01-01

45

L1CAM whole gene deletion in a child with L1 syndrome.  

PubMed

L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2. PMID:24668863

Chidsey, Brandalyn A; Baldwin, Erin E; Toydemir, Reha; Ahles, Lauren; Hanson, Heather; Stevenson, David A

2014-06-01

46

Six cases of cryptic subtelomeric translocations in four families: the use of subtelomeric FISH probes as a diagnostic tool.  

PubMed

Finding the diagnosis in children with mental retardation and a normal karyotype, whether or not associated with dysmorphic features, is important for defining an eventual syndrome and for genetic counselling of the families. Telomeric re-arrangements may be a common and underestimated-to-date cause of non-syndromic mental retardation. Using a FISH-based approach combining subtelomeric probes, we report the detection of 4 cases of cryptic translocations t(2;10)(p25.3;q26.3), t(4;17)(p16.2;q25), t(4;20)(p16.2;q13) and t(5;7)(p15.3;q36) associated with MR and dysmorphic features. We discuss the usefulness of subtelomeric FISH in children with unexplained delayed psychomotor development, when the genetic cause remains unknown and the karyotype is normal. PMID:16719273

Paoloni-Giacobino, A; Dahoun, S; Briault, S; Chalumeau, A; Till, M; Morraine, C; Lespinasse, J

2006-01-01

47

Chromosome 22q11.2 deletion in a boy with Opitz (G/BBB) syndrome  

SciTech Connect

This report is on a 14-month-old boy with manifestations of Opitz (G/BBB) syndrome in whom a 22q11.2 deletion was found. Deletion analysis was requested because of some findings in this patient reminiscent of velocardiofacial (VCF) syndrome. The extent of aspiration and of respiratory symptoms in this child is not usually seen in VCF syndrome. Opitz syndrome maps to at least two loci, one on Xp, the other on 22q11.2. 12 refs., 2 figs.

Fryburg, J.S.; Lin, K.Y.; Golden, W.L. [Univ. of Virginia Health Sciences Center, Charlottesville, VA (United States)] [Univ. of Virginia Health Sciences Center, Charlottesville, VA (United States)

1996-03-29

48

Maladaptive Behavior Differences in Prader-Willi Syndrome Due to Paternal Deletion versus Maternal Uniparental Disomy.  

ERIC Educational Resources Information Center

This study compared maladaptive behavior in 23 people with Prader-Willi syndrome due to paternal deletion and in 23 age- and gender-matched subjects with maternal uniparental disomy. Controlling for IQs, the deletion cases showed significantly higher maladaptive ratings, more symptom-related distress, and more behavior problems. Findings suggest a…

Dykens, Elisabeth M.; King, Bryan H.; Cassidy, Suzanne B.

1999-01-01

49

Lower Prepulse Inhibition in Children With the 22q11 Deletion Syndrome  

PubMed Central

Objective The 22q11 deletion syndrome is associated with a range of possible physical anomalies, probable ongoing learning disabilities, and a specific constellation of neuropsychological deficits, including impairments in selective and executive visual attention, working memory, and sensorimotor functioning. It has been estimated that 25% of the children with 22q11 deletion syndrome go on to develop schizophrenia in late adolescence or adulthood. This is of urgent concern. Specification of early brain network vulnerabilities may provide a basis for early intervention while indicating critical links between genes and severe psychiatric illness. Neuropsychological studies of children with 22q11 deletion syndrome have implicated an array of potentially aberrant brain pathways. This study was conducted to determine whether preattentive processing (“sensorimotor gating”) deficits are present in this population. Method The authors administered a test of prepulse inhibition to 25 children with 22q11 deletion syndrome and their 23 sibling comparison subjects, ages 6–13. It was predicted that the children with 22q11 deletion syndrome would have lower prepulse inhibition than the comparison subjects. Results Prepulse inhibition in the children with 22q11 deletion syndrome (26.06%) was significantly less than that of the sibling comparison subjects (46.41%). Secondary analyses suggested that this decrement did not reflect developmental delay, and lower prepulse inhibition was associated with particular subsyndromal symptoms in some children. Conclusions Sensorimotor gating is lower in children with 22q11 deletion syndrome. These findings may indicate specific brain circuits that are anomalous in 22q11 deletion syndrome. PMID:15930057

Sobin, Christina; Kiley-Brabeck, Karen; Karayiorgou, Maria

2009-01-01

50

Molecular cytogenetic detection of chromosome 15 deletions in patients with Prader-Willi and Angelman syndromes  

SciTech Connect

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct genetic disorders involving alterations of chromosome 15q11-q13. Approximately 75% of individuals with PWS and AS have deletions within 15q11-q13 by molecular analysis. We have evaluated fluorescence in situ hybridization (FISH) for the clinical laboratory detection of del(15)(q11q13) using the cosmid probes D15S11 and GABRB3 (ONCOR, Gaithersburg, NY). 4/4 PWS and 1/1 AS patients previously identified as having cytogenetic deletions were deleted for both probes. In a prospectively ascertained series of 54 patient samples referred to rule out either PWS or AS, 8 were deleted for D15S11 and GABRB3. In addition, an atypical deletion patient with PWS was also identified who was found to be deleted for GABRB3 but not D15S11. The SNRPN locus was also deleted in this patient. Only 4 of the 9 patient samples having molecular cytogenetic deletions were clearly deleted by high resolution banding (HRB) analysis. The microscopic and submicroscopic deletions have been confirmed by dinucleotide (CA) repeat analysis. Microsatellite polymorphism analysis was also used to demonstrate that five non-deletion patients in this series had biparental inheritance of chromosome 15, including region q11-q13. Deletions were not detected by either HRB, FISH or microsatellite polymorphism analysis in samples obtained from parents of the deletion patients. Methylation studies of chromosome 15q11-q13 are in progress for this series of PWS and AS families. FISH analysis of chromosome 15q11-q13 in patients with PWS and AS is a rapid, sensitive and reliable method for deletion detection.

Chadwick, D.E.; Weksberg, R.; Shuman, C. [Hospital for Sick Children, Toronto (Canada)] [and others

1994-09-01

51

Diverse deletions in the growth hormone receptor gene cause growth hormone insensitivity syndrome.  

PubMed

Growth hormone insensitivity syndrome (GHIS; also known as Laron syndrome), is characterized by severe postnatal growth failure and normal growth hormone. The syndrome is frequently caused by point mutations in the growth hormone receptor gene (GHR). Here we report five families with GHIS and partial deletions of the GHR gene. The deletion breakpoints were sequenced and PCR-based diagnostic tests were developed. In a Cambodian family, a novel deletion removed part of exon 5 and 1.2 kb of the preceding intron. The deletion occurred by recombination within four identical nucleotides. In the mutant transcript, skipping of the truncated exon 5 leads to a frameshift and premature termination codon (PTC). A previously reported discontinuous deletion of GHR exons 3, 5, and 6 was identified in three Oriental Jewish families. An unaffected individual was heterozygous for the exon 5 and 6 deletion, but homozygously deleted for exon 3 suggesting that the exon 3 deletion is a polymorphism. The pathogenic deletion of exons 5 and 6 spans about 7.5 kb. Sequence analysis of the breakpoints revealed an imperfect junction between introns 4 and 6, with a four basepair insertion. A novel deletion of 13 nucleotides within exon 9 was identified in a Caucasian girl with GHIS who carries the I153T missense mutation on her other allele. The exon 9 deletion leads to a frameshift and PTC. The predicted protein retains the transmembrane domain and a short cytoplasmic tail. Four family members in three generations were carriers of this deletion, but only two of them were below normal for height, suggesting that this mutation by itself does not act as a dominant negative, as was reported for two other GHR mutations which lead to truncation of the intracellular domain. PMID:11013443

Gastier, J M; Berg, M A; Vesterhus, P; Reiter, E O; Francke, U

2000-10-01

52

The Neural Correlates of Non-Spatial Working Memory in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)  

ERIC Educational Resources Information Center

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant…

Kates, Wendy R.; Krauss, Beth R.; AbdulSabur, Nuria; Colgan, Deirdre; Antshel, Kevin M.; Higgins, Anne Marie; Shprintzen, Robert J.

2007-01-01

53

Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome  

SciTech Connect

Mendelian inherited disorders to deletions of adjacent genes on a chromosome have been described as contiguous gene syndromes. Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome have been found as isolated entities or associated in various combination in 27 patients with interstitial and terminal deletions involving the distal short are of the X chromosome. The use of cDNA and genomic probes from the Xp22-pter region allowed us to identify 12 different deletion intervals and to confirm, and further refine, the chromosomal assignment of X-linked recessive chondrodysplasia punctata and Kallmann syndrome genes. A putative pseudoautosomal gene affecting height and an X-linked nonspecific mental retardation gene have been tentatively assigned to specific intervals. The deletion panel described is a useful tool for mapping new sequences and orienting chromosome walks in the region.

Ballabio, A.; Andria, G. (Univ. of Reggio Calabria, Catanzaro (Italy)); Bardoni, B.; Fraccaro, M.; Maraschio, P.; Zuffardi, O.; Guioli, S.; Camerino, G. (Univ. of Pavia (Italy)); Carrozzo, R. (Univ. of Naples (Italy)); Bick, D.; Campbell, L. (Univ. of Texas, San Antonio (USA)); Hamel, B. (Univ. of Nijmegen (Netherlands)); Ferguson-Smith, M.A. (Univ. of Cambridge (England)); Gimelli, G. (G. Gaslini Institute, Genoa (Italy))

1989-12-01

54

Deletion of locus D15S113 in a mother and son without features of Angelman syndrome  

Microsoft Academic Search

Deletions of the proximal long arm of chromosome 15 result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The minimal critical deletion region for Angelman syndrome has been reported to include D15S74 (B1.5), D15S10 (TD3-21), and D15S113 (LS6-1). We report a mother and son who have deletions that include D15S113 but who

R. C. Michaelis; J. C. Tarleton; T. A. Donlon; R. J. Simensen

1994-01-01

55

[Scoliosis in children with chromosome 22q11.2 deletion syndrome].  

PubMed

Chromosome 22q11.2 deletion syndrome (22q11DS) is a term used to describe a syndrome that consists of several clinical phenotypes, for example the DiGeorge syndrome, velocardiofacial syndrome and conotruncal anomaly face syndrome. These phenotypes share a common cause, i.e. deletion of a part of chromosome 22. An important clinical manifestation of this condition is scoliosis, which is estimated to occur in 15-50% of patients. We present three cases of children with scoliosis detected in early childhood. Two children were treated surgically because of progression of the deformity; in the third child surgery is being postponed as long as possible to allow further growth. We advise that every patient with 22q11DS should be screened for scoliosis. Furthermore, genetic counselling is required in all cases of scoliosis combined with distinct phenotypical characteristics. PMID:22278037

Colo, Dino; Kruyt, Mayo C; Timmers-Raaijmaakers, Brigitte C M S; Castelein, René M

2012-01-01

56

Large Deletion in KCNQ1 Identified in a Family with Jervell and Lange-Nielsen Syndrome  

PubMed Central

Long QT syndrome (LQTS) is a genetically heterogeneous disorder associated with sequence variations in more than 10 genes; in some cases, it is caused by large deletions or duplications among the main, known LQTS-associated genes. Here, we describe a 14-month-old Korean boy with congenital hearing loss and prolonged QT interval whose condition was clinically diagnosed as Jervell and Lange-Nielsen syndrome (JLNS), a recessive form of LQTS. Genetic analyses using sequence analysis and multiplex ligation-dependent probe amplification (MLPA) assay revealed a large deletion spanning exons 7-10 as well as a frameshift mutation (c.1893dup; p.Arg632Glnfs*20). To our knowledge, this is the first report of a large deletion in KCNQ1 identified in JLNS patients. This case indicates that a method such as MLPA, which can identify large deletions or duplications needs to be considered in addition to sequence analysis to diagnose JLNS. PMID:25187895

Sung, Ji Yeon; Bae, Eun Jung; Park, Seungman; Kim, So Yeon; Hyun, Ye Jin; Park, Sung Sup

2014-01-01

57

Candidate Genes and the Behavioral Phenotype in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk…

Prasad, Sarah E.; Howley, Sarah; Murphy, Kieran C.

2008-01-01

58

Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q  

SciTech Connect

Deletion 11q23{r_arrow}qter and duplication 12q23{r_arrow}qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23{r_arrow}24 in the cause of the neuroblastoma is discussed. 18 refs., 2 figs., 1 tab.

Koiffmann, C.P.; Vianna-Morgante, A.M.; Wajntal, A. [Univ. of Sao Paulo (Brazil)] [and others

1995-07-31

59

Prenatal diagnosis of interstitial deletion of 17(p11.2p11.2) (Smith-Magenis Syndrome)  

SciTech Connect

Interstitial deletion of 17p11.2 is associated with Smith-Magenis syndrome. This is a recognizable chromosomal deletion syndrome, characterized by brachycephaly, midface hypoplasia, growth and mental retardation, behavioral problems, and ocular abnormalities. Molecular analysis indicates it is a contiguous gene syndrome. Over 50 patients have been reported since the deletion was first described by Smith et al. [1982]. Cases include one with mosaicism and a familial example. None were prenatally diagnosed. The authors report on the prenatal detection of interstitial deletion of 17p11.2. 11 refs., 1 fig.

NONE

1994-01-15

60

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients  

SciTech Connect

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

Juyal, R.C.; Figuera, L.E.; Hauge, X. [Baylor College of Medicine, Houston, TX (United States)] [and others

1996-05-01

61

Screening for minute deletions in patients with suspected cri-du-chat syndrome and apparently normal karyotype  

Microsoft Academic Search

Measurement studies were carried out on the B-group chromosomes in three patients with suspected cri-du-chat syndrome, four karyotypically confirmed cases of the syndrome and three normal subjects. None of the propositi showed a detectable short-arm deletion. Within the four cases with obvious short arm deletion the amount of the deletion varies to a high degree. In addition to the technique

H. Hoehn; W. Engel

1969-01-01

62

Molecular characterization of a deletion in the HPRT1 gene in a patient with Lesch-Nyhan syndrome.  

PubMed

Lesch-Nyhan syndrome is caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT) encoded by HPRT1. About 20% of patients have a deletion of HPRT1 and large deletions of HPRT1 are not always fully characterized at the molecular level. Here, we report on a case of Lesch-Nyhan syndrome with a 33-kb deletion involving exon 1 of HPRT1. This novel mutation is caused by a nonhomologous recombination between different classes of interspersed repetitive DNA. PMID:22132985

Taniguchi, A; Yamada, Y; Hakoda, M; Sekita, C; Kawamoto, M; Kaneko, H; Yamanaka, H

2011-12-01

63

Genotype-phenotype correlation in 22q11.2 deletion syndrome  

PubMed Central

Background The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods. PMID:23245648

2012-01-01

64

Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature  

PubMed Central

Background Terminal deletions of chromosome 4q are associated with a broad spectrum of phenotypes including cardiac, craniofacial, digital, and cognitive impairment. The rarity of this syndrome renders genotype-phenotype correlation difficult, which is further complicated by the widely different phenotypes observed in patients sharing similar deletion intervals. Case presentation Herein, we describe a boy with congenital hearing impairment and a variety of moderate syndromic features that prompted SNP array analysis disclosing a heterozygous 6.9 Mb deletion in the 4q35.1q35.2 region, which emerged de novo in the maternal germ line. Conclusion In addition to the index patient, we review 35 cases from the literature and DECIPHER database to attempt genotype-phenotype correlations for a syndrome with great phenotypic variability. We delineate intervals with recurrent phenotypic overlap, particularly for cleft palate, congenital heart defect, intellectual disability, and autism spectrum disorder. Broad phenotypic presentation of the terminal 4q deletion syndrome is consistent with incomplete penetrance of the individual symptoms. PMID:24962056

2014-01-01

65

Subtypes in 22q11.2 Deletion Syndrome Associated with Behaviour and Neurofacial Morphology  

ERIC Educational Resources Information Center

22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among…

Sinderberry, Brooke; Brown, Scott; Hammond, Peter; Stevens, Angela F.; Schall, Ulrich; Murphy, Declan G. M.; Murphy, Kieran C.; Campbell, Linda E.

2013-01-01

66

Children with Chromosome 22q11.2 Deletion Syndrome Exhibit Impaired Spatial Working Memory  

ERIC Educational Resources Information Center

Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with…

Wong, Ling M.; Riggins, Tracy; Harvey, Danielle; Cabaral, Margarita; Simon, Tony J.

2014-01-01

67

Domain Specific Attentional Impairments in Children with Chromosome 22Q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

One of the defining cognitive characteristics of the chromosome 22q deletion syndrome (DS22q11.2) is visuospatial processing impairments. The purpose of this study was to investigate and extend the specific attentional profile of children with this disorder using both an object-based attention task and an inhibition of return task. A group of…

Bish, Joel P.; Chiodo, Renee; Mattei, Victoria; Simon, Tony J.

2007-01-01

68

Updating the profile of C-terminal MECP2 deletions in Rett syndrome  

PubMed Central

Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region. Conclusion In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome. PMID:19914908

Bebbington, A; Percy, A; Christodoulou, J; Ravine, D; Ho, G; Jacoby, P; Anderson, A; Pineda, M; Ben Zeev, B; Bahi-Buisson, N; Smeets, E; Leonard, H

2014-01-01

69

VISUOSPATIAL AND NUMERICAL COGNITIVE DEFICITS IN CHILDREN WITH CHROMOSOME 22Q11.2 DELETION SYNDROME  

PubMed Central

This article presents some of the earliest evidence of visuospatial and numerical cognitive deficits in children with the chromosome 22q11.2 deletion syndrome; a common but ill-understood genetic disorder resulting in medical complications, cognitive impairment, and brain morphologic changes. Relative to a group of typically developing controls, deleted children performed more poorly on tests of visual attentional orienting, visual enumeration and relative numerical magnitude judgment. Results showed that performance deficits in children with the deletion could not be explained by a global deficit in psychomotor speed. Instead, our findings are supportive of the hypothesis that visuospatial and numerical deficits in children with the chromosome 22q11.2 deletion are due, at least in part, to posterior parietal dysfunction. PMID:15714897

Simon, Tony J.; Bearden, Carrie E.; Mc-Ginn, Donna McDonald; Zackai, Elaine

2015-01-01

70

An Interstitial 15q11-q14 Deletion: Expanded Prader-Willi Syndrome Phenotype  

PubMed Central

We present an infant girl with a de novo interstitial deletion of the chromosome 15q11-q14 region, larger than the typical deletion seen in Prader-Willi syndrome (PWS). She presented with features seen in PWS including hypotonia, a poor suck, feeding problems and mild micrognathia. She also presented with features not typically seen in PWS such as preauricular ear tags, a high arched palate, edematous feet, coarctation of the aorta, a PDA and a bicuspid aortic valve. G-banded chromosome analysis showed a large de novo deletion of the proximal long arm of chromosome 15 confirmed using FISH probes (D15511 and GABRB3). Methylation testing was abnormal and consistent with the diagnosis of PWS. Because of the large appearing deletion by karyotype analysis, an array comparative genomic hybridization (CGH) was performed. A 12.3 Mb deletion was found which involved the 15q11-q14 region containing approximately 60 protein coding genes. This rare deletion was approximately twice the size of the typical deletion seen in PWS and involved the proximal breakpoint BP1 and the distal breakpoint was located in the 15q14 band between previously recognized breakpoints BP5 and BP6. The deletion extended slightly distal to the AVEN gene including the neighboring CHRM5 gene. There is no evidence that the genes in the 15q14 band are imprinted; therefore, their potential contribution in this patient's expanded Prader-Willi syndrome phenotype must be a consequence of dosage sensitivity of the genes or due to altered expression of intact neighboring genes from a position effect. PMID:20082457

Butler, Merlin G.; Bittel, Douglas C.; Kibiryeva, Nataliya; Cooley, Linda D.; Yu, Shihui

2009-01-01

71

Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome  

PubMed Central

Background 2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition. Case presentation We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216-242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33–p36.32 (chr1:834,101–2,567,832) and 20p12.3 (chr20:5,425,762–5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3. Conclusion This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33–p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications. PMID:24755370

2014-01-01

72

A novel deletion in proximal 22q associated with cardiac septal defects and microcephaly: a case report  

PubMed Central

Background Proximal 22q is rich in low copy repeats (LCRs) which mediate non-allelic homologous recombination and give rise to deletions and duplications of varying size depending on which LCRs are involved. Methods A child with multiple septal defects and other congenital anomalies was investigated for genome imbalance using multiplex ligation-dependent probe amplification (MLPA) for subtelomeres and microdeletion loci, followed by array comparative genomic hybridization (CGH) using oligonucleotide arrays with 44,000 probes across the genome. Results MLPA identified a single probe deletion in the SNAP29 gene within band 22q11.21. Follow-up array CGH testing revealed a ~1.4-Mb deletion from 19,405,375 bp to 20,797,502 bp, encompassing 28 genes. Conclusion This deletion is likely to be causally associated with the proband's congenital anomalies. Previous publications describing deletions in proximal 22q have reported deletions between LCRs 1 to 4, associated with 22q11 deletion syndrome; in addition, deletions between LCRs 4 and 6 have been described associated with "distal 22q11 deletion syndrome". To our knowledge, this is the first deletion which spans LCR4 and is not apparently mediated by LCRs. Comparison of the phenotypes found in conjunction with previously reported deletions, together with the function and expression patterns of genes in the deleted region reported here, suggests that haploinsufficiency for the Crk-like (CRKL) gene may be responsible for the reported cardiac abnormalities. PMID:19239688

Ogilvie, Caroline Mackie; Ahn, Joo Wook; Mann, Kathy; Roberts, Roland G; Flinter, Frances

2009-01-01

73

Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome.  

PubMed Central

Miller-Dieker syndrome (MDS), a disorder manifesting the severe brain malformation lissencephaly ("smooth brain"), is caused, in the majority of cases, by a chromosomal microdeletion of the distal short arm of chromosome 17. Using human chromosome 17-specific DNA probes, we have begun a molecular dissection of the critical region for MDS. To localize cloned DNA sequences to the MDS critical region, a human-rodent somatic cell hybrid panel was constructed which includes hybrids containing the abnormal chromosome 17 from three MDS patients with deletions of various sizes. Three genes (myosin heavy chain 2, tumor antigen p53, and RNA polymerase II) previously mapped to 17p were excluded from the MDS deletion region and therefore are unlikely to play a role in its pathogenesis. In contrast, three highly polymorphic anonymous probes, YNZ22.1 (D17S5), YNH37.3 (D17S28), and 144-D6 (D17S34), were deleted in each of four patients with visible deletions, including one with a ring chromosome 17 that is deleted for a portion of the single telomeric prometaphase subband p13.3. In two MDS patients with normal chromosomes, a combination of somatic cell hybrid, RFLP, and densitometric studies demonstrated deletion for YNZ22.1 and YNH37.3 in the paternally derived 17's of both patients, one of whom is also deleted for 144-D6. The results indicate that MDS can be caused by submicroscopic deletion and raises the possibility that all MDS patients will prove to have deletions at a molecular level. The two probes lie within a critical region of less than 3,000 kb and constitute potential starting points in the isolation of genes implicated in the severe brain maldevelopment in MDS. Images Figure 2 Figure 3 Figure 4 PMID:3189330

vanTuinen, P; Dobyns, W B; Rich, D C; Summers, K M; Robinson, T J; Nakamura, Y; Ledbetter, D H

1988-01-01

74

Mitochondrial DNA deletion in a patient with combined features of Leigh and Pearson syndromes  

SciTech Connect

We describe a heteroplasmic 4237 bp mitochondrial DNA (mtDNA) deletion in an 11 year old girl who has suffered from progressive illness since birth. She has some features of Leigh syndrome (global developmental delay with regression, brainstem dysfunction and lactic acidosis), together with other features suggestive of Pearson syndrome (history of pancytopenia and failure to thrive). The deletion was present at a level greater than 50% in skeletal muscle, but barely detectable in skin fibroblasts following Southern blot analysis, and only observed in blood following PCR analysis. The deletion spanned nt 9498 to nt 13734, and was flanked by a 12 bp direct repeat. Genes for cytochrome c oxidase subunit III, NADH dehydrogenase subunits 3, 4L, 4 and 5, and tRNAs for glycine, arginine, histidine, serine({sup AGY}) and leucine({sup CUN}) were deleted. Southern blotting also revealed an altered Apa I restriction site which was shown by sequence analysis to be caused by G{r_arrow}A nucleotide substitution at nt 1462 in the 12S rRNA gene. This was presumed to be a polymorphism. No abnormalities of mitochondrial ultrastructure, distribution or of respiratory chain enzyme complexes I-IV in skeletal muscle were observed. Mitochondrial disorders with clinical features overlapping more than one syndrome have been reported previously. This case further demonstrates the difficulty in correlating observed clinical features with a specific mitochondrial DNA mutation.

Blok, R.B.; Thorburn, D.R.; Danks, D.M. [Royal Children`s Hospital, Melbourne (Australia)] [and others

1994-09-01

75

Genotype/phenotype correlation in women with nonmosaic X chromosome deletions and Turner syndrome  

SciTech Connect

Turner syndrome is a complex human developmental disorder associated with the absence of the second sex chromosome (monosomy X). Cardinal features of the Turner phenotype include high intrauterine lethality, growth retardation, gonadal failure, and the variable presence of specific somatic abnormalities such as webbed neck, lymphedema, and skeletal abnormalities. Recent observations support the hypothesis that the phenotype associated with monosomy X results from haploid dosage of genes common the X and Y chromosomes that escape X-inactivation ({open_quotes}Turner genes{close_quotes}). Apart from a locus causing short stature that maps to the pseudoautosomal region on the distal short arm, the location of X-linked Turner genes is not known. Karyotype/phenotype correlations in women with partial X deletions have been inconsistent. However, previous studies have focused on sporadic sex chromosome aberrations and may have been confounded by occult mosaicism. In addition, mapping of deletions was limited by the resolution of cytogenetic techniques. I am reexamining genotype/phenotype correlations in partial X monosomy, focusing on a subset of cases in which mosaicism is highly unlikely (e.g., unbalanced X-autosome translocations, familial X deletions), and using molecular techniques to map deletions. I have collected eight cases of nonmosaic X deletions in women with varied manifestations of Turner syndrome. Cytogenetic data suggests that genes responsible for Turner anatomic abnormalities may lie within a critical region of the very proximal portion of the short arm (Xp11). Molecular characterization of the deletions is in progress. Methods include (1) fluorescence in situ hybridization of metaphase spreads from patient-derived cell lines, using cosmid probes that map to known locations on Xp, and (2) sequence tagged site (STS) content mapping of somatic cell hybrids retaining the deleted X chromosomes derived from these cell lines.

Zinn, A.R. [Univ. of Texas Southwestern Medical School, Dallas, TX (United States)

1994-09-01

76

Comparison of phenotype in uniparental disomy and deletion Prader-Willi syndrome: Sex specific differences  

SciTech Connect

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P<.001) limited to the UPD group with a predominance (68%) of males. An equal number of males and females was observed in the deletion group. When analyzed by sex, several significant differences between the UPD and deletion groups were observed. Female UPD patients were found to be less severely affected than female deletion patients in terms of length of gavage feeding and a later onset of hyperphagia. Although these traits are likely to be influenced by external factors, they may reflect a milder presentation of female UPD patients which could explain the observed sex bias by causing under-ascertainment of female UPD. Alternatively, there may be an effect of sex on either early trisomy 15 survival or the probability of somatic loss of a chromosome from a trisomic conceptus. 26 refs., 1 tab.

Mitchell, J.; Langlois, S.; Robinson, W.P. [Univ. of British Columbia, Vancouver (Canada)] [and others] [Univ. of British Columbia, Vancouver (Canada); and others

1996-10-16

77

Branchio-oto-renal syndrome caused by partial EYA1 deletion due to LINE-1 insertion.  

PubMed

A 7-year-old Japanese girl with conductive deafness and preauricular fistulae developed proteinuria. She had renal insufficiency, and ultrasound revealed bilateral small kidneys. These findings indicated that she had branchio-oto-renal (BOR) syndrome. In the present patient, we identified, by using multiplex ligation-dependent probe amplification (MLPA) analysis, a heterozygous EYA1 gene deletion comprising at least exons 5 to 7. In her parents, we did not detect any deletion in EYA1 by MLPA, so the deletion was a de novo mutation. PCR analysis and sequencing of patient DNA revealed a heterozygous approximately 17 kb EYA1 deletion starting from the eight last bases of exon 4 and proceeding to base 1,217 of intron 7. Furthermore, in place of this deleted region was inserted a 3756-bp-long interspersed nuclear elements-1 (LINE-1, L1). Accordingly, RT-PCR showed that exons 4-7 were not present in EYA1 mRNA expressed from the mutated allele. Although there are reports of L1 element insertion occurring in various human diseases, this is the first report of a large EYA1 deletion in combination with L1 element insertion. PMID:20130917

Morisada, Naoya; Rendtorff, Nanna Dahl; Nozu, Kandai; Morishita, Takahiro; Miyakawa, Takayuki; Matsumoto, Tohru; Hisano, Satoshi; Iijima, Kazumoto; Tranebjaerg, Lisbeth; Shirahata, Akira; Matsuo, Masafumi; Kusuhara, Koichi

2010-07-01

78

Secondary Immunologic Consequences in Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)  

PubMed Central

Clinical evidence suggests that patients with Chromosome 22q11.2 deletion (Ch22q11.2D) have an increased prevalence of atopic and autoimmune disease and this has been without explanation. We hypothesized that the increase in atopy was due to homeostatic proliferation of T cells leading to a Th2 skew. We performed intracellular cytokine staining to define Th1/Th2 phenotypes in toddlers (early homeostatic proliferation) and adults (post homeostatic proliferation) with this syndrome. To attempt to understand the predisposition to autoimmunity we performed immunophenotyping analyses to define Th17 cells and B cell subsets. Adult Ch22q11.2D patients had a higher percentage of IL-4+CD4+ T cells than controls. Th17 cells were no different in patients and controls. In addition, adult Ch22q11.2D syndrome patients had significantly lower switched memory B cells, suggesting a dysregulated B cell compartment. These studies demonstrate that the decrement in T cell production has secondary consequences in the immune system, which could mold the patients’ clinical picture. PMID:20472505

Zemble, R.; Prak, E. Luning; McDonald, K.; McDonald-McGinn, D.; Zackai, E.; Sullivan, K.

2010-01-01

79

An Amino Acid Deletion in SZT2 in a Family with Non-Syndromic Intellectual Disability  

PubMed Central

Autosomal recessive intellectual disability (ID) is characterized by extensive genetic heterogeneity. Recently, three mutations in SZT2 were reported in two unrelated children with unexplained infantile epileptic encephalopathy with severe ID. Here we report a European American family with three children having non-syndromic mild or moderate ID without seizures. Whole-exome sequencing of three affected siblings revealed a three base pair deletion (c.4202_4204delTTC) located in a 19 mb autozygous region on chromosome 1, leading to an amino acid deletion (p.Phe1401del) in SZT2. All three children were homozygous for the deletion and their parents were heterozygous as expected in autosomal recessive inheritance. SZT2 is highly expressed in neuronal tissues and regulates seizure threshold and neuronal excitation in mice. We conclude that the disruption of SZT2 with some residual function might lead to mild or moderate ID without seizures. PMID:24324832

Falcone, Michelle; Yariz, Kemal O.; Ross, David B.; Foster, Joseph; Menendez, Ibis; Tekin, Mustafa

2013-01-01

80

Neuropsychological function in a child with 18p deletion syndrome: a case report.  

PubMed

We report the neuropsychological profile of a 4-year-old boy with the rare 18p deletion syndrome. We used a battery of standardized tests to assess his development in intellect, language, visuomotor integration, academic readiness, socialization, and emotional and behavioral health. The results showed borderline intellectual function except for low average nonverbal reasoning skills. He had stronger receptive than expressive language skills, although both were well below his age group. He had impaired visuomotor integration and pre-academic skills such as letter identification. Emotional and behavioral findings indicated mild aggressiveness, anxiety, low frustration tolerance, and executive function weaknesses, especially at home. Interestingly, he showed social strengths, responding to joint attention and sharing enjoyment with his examiner. With its assessment of development in many domains, this case report is among the first to characterize the neuropsychological and psychiatric function of a young child with 18p deletion syndrome. We discuss the implications of our findings for clinical practice. PMID:25237747

Willoughby, Brian L; Favero, Marcus; Mochida, Ganeshwaran H; Braaten, Ellen B

2014-09-01

81

Subtelomeric chromosomal rearrangements in a large cohort of unexplained intellectually disabled individuals in Indonesia: A clinical and molecular study  

PubMed Central

CONTEXT: Unbalanced subtelomeric chromosomal rearrangements are often associated with intellectual disability (ID) and malformation syndromes. The prevalence of such rearrangements has been reported to be 5-9% in ID populations. AIMS: To study the prevalence of subtelomeric rearrangements in the Indonesian ID population. MATERIALS AND METHODS: We tested 436 subjects with unexplained ID using multiplex ligation dependent probe amplification (MLPA) using the specific designed sets of probes to detect human subtelomeric chromosomal imbalances (SALSA P070 and P036D). If necessary, abnormal findings were confirmed by other MLPA probe kits, fluorescent in situ hybridization or Single Nucleotide Polymorphism array. RESULTS: A subtelomeric aberration was identified in 3.7% of patients (16/436). Details on subtelomeric aberrations and confirmation analyses are discussed. CONCLUSION: This is the first study describing the presence of subtelomeric rearrangements in individuals with ID in Indonesia. Furthermore, it shows that also in Indonesia such abnormalities are a prime cause of ID and that in developing countries with limited diagnostic services such as Indonesia, it is important and feasible to uncover the genetic etiology in a significant number of cases with ID. PMID:24019618

Mundhofir, Farmaditya E. P.; Nillesen, Willy M.; Van Bon, Bregje W. M.; Smeets, Dominique; Pfundt, Rolph; van de Ven-Schobers, Gaby; Ruiterkamp-Versteeg, Martina; Winarni, Tri I.; Hamel, Ben C. J.; Yntema, Helger G.; Faradz, Sultana M. H.

2013-01-01

82

Safety of Live Viral Vaccines in Patients With Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome\\/Velocardiofacial Syndrome)  

Microsoft Academic Search

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Never- theless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syn- drome and is associated with thymic hypoplasia and diminished T-cell

Elena E. Perez; Aleksandra Bokszczanin; Elaine H. Zackai; Kathleen E. Sullivan

83

Christianson syndrome in a patient with an interstitial Xq26.3 deletion.  

PubMed

Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene. PMID:21932316

Tzschach, Andreas; Ullmann, Reinhard; Ahmed, Alischo; Martin, Thomas; Weber, Georg; Decker-Schwering, Oliver; Pauly, Fernand; Shamdeen, Mohammed Ghiath; Reith, Wolfgang; Oehl-Jaschkowitz, Barbara

2011-11-01

84

Prodromal symptoms in adolescents with 22q11.2 deletion syndrome and schizotypal personality disorder  

Microsoft Academic Search

Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research

D. I. Shapiro; J. F. Cubells; O. Y. Ousley; K. Rockers; E. F. Walker

2011-01-01

85

The Neuropsychology of 22q11 Deletion Syndrome. A Neuropsychiatric Study of 100 Individuals  

ERIC Educational Resources Information Center

The primary objective of this study was to study the impact of ASD/ADHD on general intellectual ability and profile, executive functions and visuo-motor skills in children and adults with 22q11 deletion syndrome (22q11DS). A secondary aim was to study if gender, age, heart disease, ASD, ADHD or ASD in combination with ADHD had an impact on general…

Niklasson, Lena; Gillberg, Christopher

2010-01-01

86

MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome.  

PubMed

Kabuki syndrome (KS) is a rare multi-system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types- two patients with mosaic small deletions, one with a mosaic whole-gene deletion, one with a multi-exon deletion and one with an intragenic multi-exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS. PMID:22901312

Banka, S; Howard, E; Bunstone, S; Chandler, K E; Kerr, B; Lachlan, K; McKee, S; Mehta, S G; Tavares, A L T; Tolmie, J; Donnai, D

2013-05-01

87

Distal Deletion of Chromosome 11q Encompassing Jacobsen Syndrome without Platelet Abnormality  

PubMed Central

Terminal 11q deletion, known as Jacobsen syndrome (JBS), is a rare genetic disorder associated with numerous dysmorphic features. We studied two cases with multiple congenital anomalies that were cytogenetically detected with deletions on 11q encompassing JBS region: 46,XX,der(11) del(11)(q24). Array comparative genomic hybridization (aCGH) analysis confirmed partial deletion of 11.8–11.9 Mb at 11q24.1q25 (case 1) and 13.9–14 Mb deletion at 11q23.3q25 together with 7.3–7.6 Mb duplication at 12q24.32q24.33 (case 2). Dysmorphism because of the partial duplication of 12q was not overtly decipherable over the Jacobsen phenotype except for a triangular facial profile. Aberrant chromosome 11 was inherited from phenotypically normal father, carrier of balanced translocation 46,XY,t(11;12)(q23.3; q24.32). In the present study, both cases had phenotypes that were milder than the ones described in literature despite having large deletion size. Most prominent features in classical JBS is thrombocytopenia, which was absent in both these cases. Therefore, detailed functional analysis of terminal 11q region is warranted to elucidate etiology of JBS and their clinical presentation. PMID:25288895

Sheth, Frenny J; Datar, Chaitanya; Andrieux, Joris; Pandit, Anand; Nayak, Darshana; Rahman, Mizanur; Sheth, Jayesh J

2014-01-01

88

Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients  

PubMed Central

Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. PMID:25057328

2014-01-01

89

Interstitial deletion of 11(p11.2p12): A newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses  

SciTech Connect

Individuals with deletions of the proximal portion of the short arm of chromosome 11 share many manifestations including mental retardation, biparietal foramina, minor facial anomalies, and multiple cartilaginous exostoses. The finding of multiple exostoses in these patients is remarkable as the disorder hereditary multiple exostoses, which is inherited in an autosomal dominant manner, has recently been mapped by linkage to three regions, including proximal 11p. We report the clinical and molecular findings in an additional patient with an 11(p11.2p12) deletion. Cytogenetic and molecular analysis demonstrated a de novo, paternally derived deletion for markers which have been shown to be tightly linked to the 11p locus (EXT2). These data support the location of EXT2 within this region and also provide information regarding the ordering of polymorphic markers on 11p. Deletion 11(p11.2p12) is a rare, yet specific, deletion syndrome involving the EXT2 locus, a gene for parietal foramina, and a mental retardation locus, and therefore can be classified as a contiguous gene deletion syndrome. 24 refs., 4 figs., 1 tab.

Potocki, L.; Shaffer, L.G. [Baylor College of Medicine, Houston, TX (United States)] [Baylor College of Medicine, Houston, TX (United States)

1996-03-29

90

A new patient with a terminal de novo 2p25.3 deletion of 1.9 Mb associated with early-onset of obesity, intellectual disabilities and hyperkinetic disorder  

PubMed Central

Terminal and interstitial deletions of 2p25.3 (size?subtelomeric deletion should be associated with syndromic obesity and MYT1L became the main candidate gene for ID and obesity since it is deleted or disrupted in all hitherto published cases. Here we described a 2p25.3 de novo terminal deletion of 1.9 Mb, of paternal origin, detected by array-CGH analysis in a girl of 4.4 years with a distinctive phenotype consisting of early-onset of obesity associated with moderate ID, and hyperkinetic disorder. The deletion disrupted MYT1L and encompassed five other OMIM genes, ACP1, TMEM18, SNTG2, TPO, and PXDN. Here, we discuss the combined functional effects of additional haploinsufficient genes, that may concur with heterozygous deletion of MYT1L, in the aetiology for syndromic obesity associated with 2p25.5 subtelomeric deletion. PMID:25126114

2014-01-01

91

Obstructive Sleep Apnea Syndrome in Children with 22q11.2 Deletion Syndrome after Operative Intervention for Velopharyngeal Insufficiency  

PubMed Central

Introduction: Surgical treatment of velopharyngeal insufficiency (VPI) in 22q11.2 deletion syndrome is often warranted. In this patient population, VPI is characterized by poor palatal elevation and muscular hypotonia with an intact palate. We hypothesize that 22q11.2 deletion patients are at greater risk of obstructive sleep apnea (OSA) after surgical correction of VPI, due, in part, to their functional hypotonia, large velopharyngeal gap size, and the need to surgically obstruct the velopharynx. Methods: We performed a retrospective analysis of patients with 22q11.2 deletion syndrome treated at a tertiary pediatric hospital between the years of 2002 and 2012. The incidence of VPI, need for surgery, post-operative polysomnogram, post-operative VPI assessment, and OSA treatments were evaluated. Results: Forty-three patients (18 males, 25 females, ages 1–14?years) fitting the inclusion criteria were identified. Twenty-eight patients were evaluated by speech pathology due to hypernasality. Twenty-one patients had insufficient velopharyngeal function and required surgery. Fifteen underwent pharyngeal flap surgery, three underwent sphincter pharyngoplasty, two underwent Furlow palatoplasty, and one underwent combined sphincter pharyngoplasty with Furlow palatoplasty. Of these, eight had post-operative snoring. Six of these underwent polysomnography (five underwent pharyngeal flap surgeries and one underwent sphincter pharyngoplasty). Four patients were found to have OSA based on the results of the polysomnography (average apnea/hypopnea index of 4.9 events/h, median?=?5.1, SD?=?2.1). Two required continuous positive airway pressure (CPAP) due to moderate OSA. Conclusion: Surgery is often necessary to correct VPI in patients with 22q11.2 deletion syndrome. Monitoring for OSA should be considered after surgical correction of VPI due to a high occurrence in this population. Furthermore, families should be counseled of the risk of OSA after surgery and the potential need for treatment with CPAP. PMID:25157342

Crockett, David Jeffrey; Goudy, Steven L.; Chinnadurai, Sivakumar; Wootten, Christopher Todd

2014-01-01

92

Oculo-facio-cardio-dental (OFCD) syndrome: The first Italian case of BCOR and co-occurring OTC gene deletion.  

PubMed

Oculo-facio-cardio-dental (OFCD) syndrome is a rare genetic disorder affecting ocular, facial, dental and cardiac systems. The syndrome is an X-linked dominant trait and it might be lethal in males. This syndrome is usually caused by mutations in the BCL6 interacting co-repressor gene (BCOR). We described a female child with mild phenotype of oculo-facio-cardio-dental syndrome. Array-comparative genomic hybridization (a-CGH) analysis revealed a de novo heterozygous deletion in the Xp11.4 region of approximately 2.3Mb, involving BCOR and ornithine carbamoyl-transferase (OTC) genes. The deletion observed was subsequently confirmed by real time PCR. In this study we report a first case with co-occurrence of BCOR and OTC genes completely deleted in OFCD syndrome. PMID:25620158

Di Stefano, C; Lombardo, B; Fabbricatore, C; Munno, C; Caliendo, I; Gallo, F; Pastore, L

2015-04-01

93

Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.  

PubMed Central

Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap. Images Figure 1 Figure 2 Figure 4 PMID:9326330

Shapira, S K; McCaskill, C; Northrup, H; Spikes, A S; Elder, F F; Sutton, V R; Korenberg, J R; Greenberg, F; Shaffer, L G

1997-01-01

94

Alagille syndrome with interstitial 20p deletion derived from maternal ins(7;20)  

SciTech Connect

We present a 6-year-old Chinese boy with Alagille syndrome and an interstitial 20p deletion, with a karyotype of 46,XY,der(20)dir ins(7;20)(q11.23;p11.23p12.2 or p12.2p13)mat. He had a peculiar face and suffered from congenital heart disease, growth retardation, severe cholestasis, hepatosplenomegaly, and impaired renal function. The karyotype of his mother showed a balanced translocation, 46,XX,dir ins(7;20)(q11.23; p11.23p12.2 or p12.2p13), and her phenotype was normal. His dead elder brother was highly suspected as another victim of Alagille syndrome. The findings in the present family suggested that if Alagille syndrome is a single gene defect, the putative gene responsible for the syndrome would not be located at the insertion breakpoints but located within the deletion extent. 18 refs., 5 figs.

Pi-Hsien Li; San-Ging Shu; Ching-Shiang Chi [Taichung Veterans General Hospital, Taiwan (China)] [and others

1996-06-28

95

Subtelomeric CTCF and cohesin binding site organization using improved subtelomere assemblies and a novel annotation pipeline.  

PubMed

Mapping genome-wide data to human subtelomeres has been problematic due to the incomplete assembly and challenges of low-copy repetitive DNA elements. Here, we provide updated human subtelomere sequence assemblies that were extended by filling telomere-adjacent gaps using clone-based resources. A bioinformatic pipeline incorporating multiread mapping for annotation of the updated assemblies using short-read data sets was developed and implemented. Annotation of subtelomeric sequence features as well as mapping of CTCF and cohesin binding sites using ChIP-seq data sets from multiple human cell types confirmed that CTCF and cohesin bind within 3 kb of the start of terminal repeat tracts at many, but not all, subtelomeres. CTCF and cohesin co-occupancy were also enriched near internal telomere-like sequence (ITS) islands and the nonterminal boundaries of subtelomere repeat elements (SREs) in transformed lymphoblastoid cell lines (LCLs) and human embryonic stem cell (ES) lines, but were not significantly enriched in the primary fibroblast IMR90 cell line. Subtelomeric CTCF and cohesin sites predicted by ChIP-seq using our bioinformatics pipeline (but not predicted when only uniquely mapping reads were considered) were consistently validated by ChIP-qPCR. The colocalized CTCF and cohesin sites in SRE regions are candidates for mediating long-range chromatin interactions in the transcript-rich SRE region. A public browser for the integrated display of short-read sequence-based annotations relative to key subtelomere features such as the start of each terminal repeat tract, SRE identity and organization, and subtelomeric gene models was established. PMID:24676094

Stong, Nicholas; Deng, Zhong; Gupta, Ravi; Hu, Sufen; Paul, Shiela; Weiner, Amber K; Eichler, Evan E; Graves, Tina; Fronick, Catrina C; Courtney, Laura; Wilson, Richard K; Lieberman, Paul M; Davuluri, Ramana V; Riethman, Harold

2014-06-01

96

Duplication 5q and deletion 9p due to a t(5;9)(q34;p23) in 2 cousins with features of Hunter-McAlpine syndrome and hypothyroidism.  

PubMed

We report on 2 similarly affected cousins with a compound imbalance resulting from a familial t(5;9)(q34;p23) and entailing both an ?17-Mb 5q terminal duplication and an ?12-Mb 9p terminal deletion as determined by G-banding, subtelomere FISH, and aCGH. The proband's karyotype was 46,XX,der(9)t(5;9)(q34;p23)mat.ish der(9)t(5;9)(q34;p23)(9pter-,5qter+).arr 5q34q35(163,328,000-180,629,000)×3, 9p24p23(194,000-12,664,000)×1. Her cousin had the same unbalanced karyotype inherited from his father. The clinical phenotype mainly consists of a distinct craniofacial dysmorphism featuring microcephaly, flat facies, down slanting palpebral fissures, small flat nose, long philtrum, and small mouth with thin upper lip. Additional remarkable findings were craniosynostosis of several sutures, craniolacunia and preaxial polydactyly in the proband and hypothyroidism in both subjects. The observed clinical constellation generally fits the phenotypic spectrum of the 5q distal duplication syndrome (known also as Hunter-McAlpine syndrome), except for the thyroid insufficiency which can likely be ascribed to the concurrent 9p deletion, as at least 4 other 9pter monosomic patients without chromosome 5 involvement had this hormonal disorder. The present observation further confirms the etiology of the HMS phenotype from gain of the 5q35?qter region, expands the clinical pictures of partial trisomy 5q and monosomy 9p, and provides a comprehensive list of 160 patients with 5q distal duplication. PMID:21063078

Vásquez-Velásquez, A I; García-Castillo, H A; González-Mercado, M G; Dávalos, I P; Raca, G; Xu, X; Dwyer, E; Rivera, H

2011-01-01

97

Deletion of locus D15S113 in a mother and son without features of Angelman syndrome  

SciTech Connect

Deletions of the proximal long arm of chromosome 15 result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The minimal critical deletion region for Angelman syndrome has been reported to include D15S74 (B1.5), D15S10 (TD3-21), and D15S113 (LS6-1). We report a mother and son who have deletions that include D15S113 but who do not have features of Angelman syndrome. D.H. is a 10-year-old white male referred for genetic evaluation due to mental retardation. He has mild to moderate mental retardation and minor dysmorphic features, including downslanting palpebral fissures, prominent nose, broad forehead, small chin, midface hypoplasia, and large ears. His mother (B.S.) has slightly downslanting palpebral fissures and a borderline intellectual deficit. Neither individual has the seizures, excessive laughter, hand clapping, ataxia or facial dysmorphism which are characteristic of Angelman syndrome. The linear order of probes mapping to 15q11-q13 is 15cen-D15S11-D15S13-D15S10-D15S113-GABRB3-D15S12-tel. The proximal border of the deletion in our patients lies between D15S10 and D15S113. The fact that these two individuals do not have Angelman syndrome, despite deletion of D15S113, suggests that the Angelman syndrome critical deletion region should be further refined to exclude the D15S113 locus. In addition, the findings of a more severe intellectual impairment in the son than in the mother suggests that the region immediately telomeric to the critical deletion region for Angelman syndrome may contain imprintable genes that influence intellectual function.

Michaelis, R.C.; Tarleton, J.C.; Donlon, T.A.; Simensen, R.J. [Greenwood Gneetic Center, SC (United States)] [and others

1994-09-01

98

Eye Gaze During Face Processing in Children and Adolescents with 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

Objective: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome with high risk for the development of psychiatric disorder. There is interest in identifying reliable markers for measuring and monitoring socio-emotional impairments in 22q11DS during development. The current study investigated eye gaze as a potential marker during a…

Glaser, Bronwyn; Debbane, Martin; Ottet, Marie-Christine; Vuilleumier, Patrik; Zesiger, Pascal; Antonarakis, Stylianos E.; Eliez, Stephan

2010-01-01

99

Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature  

Microsoft Academic Search

Rett syndrome is a severe neurodegenerative disorder characterized by acquired microcephaly, communication dysfunction, psychomotor regression, seizures and stereotypical hand movements. Mutations in methyl CpG binding protein 2 (MECP2) are identified in most patients with classic Rett syndrome. Genetic studies in patients with a Rett variant have expanded the spectrum of underlying genetic etiologies. Recently, a deletion encompassing several genes in

Francois Dominique Jacob; Vijay Ramaswamy; John Andersen; Francois V Bolduc

2009-01-01

100

Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia  

ERIC Educational Resources Information Center

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

2010-01-01

101

Fifty microdeletions among 112 cases of sotos syndrome: Low copy repeats possibly mediate the common deletion  

SciTech Connect

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploin sufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45 percent) and 16 point mutations (14 percent) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52 percent) of the 95 Japanese patients and only one (6 percent) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion. This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

Kurotaki, Naohiro; Harada, Naoki; Shimokawa, Osamu; Miyake, Noriko; Kawame, Hiroshi; Uetake, Kimiaki; Makita, Yoshio; Kondoh, Tatsuro; Ogata, Tsutomu; Hasegawa, Tomoko; Nagai, Toshiro; Ozaki, Takao; Touyama, Mayumi; Shenhav, Ruthie; Ohashi, Hirofumi; Medne, Livija; Shiihara, Takashi; Ohtsu, Shigeyuki; Kato, Zen-ichiro; Okamoto, Nobuhiko; Nishimoto, Junji; Lev, Dorit; Miyoshi, Yoko; Ishikiriyama, Satoshi; Sonoda, Tohru; Sakazume, Satoru; Fukushima, Yoshimitsu; Kurosawa, Kenji; Cheng, Jan-Fang; Yoshiura, Koh-ichiro; Ohta, Tohru; Kishino, Tatsuya; Niikawa, Norio; Matsumoto, Naomichi

2003-04-15

102

Mitochondral localization and function of a subset of 22q11 Deletion Syndrome candidate genes  

PubMed Central

Six genes in the 1.5 MB region of chromosome 22 deleted in DiGeorge/22q11 Deletion Syndrome—Mrpl40, Prodh, Slc25a1, Txnrd2, T10, and Zdhhc8—encode mitochondrial proteins. All six genes are expressed in the brain, and maximal expression coincides with peak forebrain synaptogenesis shortly after birth. Furthermore, their protein products are associated with brain mitochondria, including those in synaptic terminals. Among the six, only Zddhc8 influences mitochondria-regulated apoptosis when overexpressed, and appears to interact biochemically with established mitochondrial proteins. Zdhhc8 has an apparent interaction with Uqcrc1, a component of mitochondrial complex III. The two proteins are coincidently expressed in presynaptic processes; however, Zdhhc8 is more frequently seen in glutamatergic terminals. 22q11 deletion may alter metabolic properties of cortical mitochondria during early post-natal life, since expression complex III components, including Uqcrc1, is significantly increased at birth in a mouse model of 22q11 deletion, and declines to normal values in adulthood. Our results suggest that altered dosage of one, or several 22q11 mitochondrial genes, particularly during early postnatal cortical development, may disrupt neuronal metabolism or synaptic signaling. PMID:18775783

Maynard, T. M.; Meechan, D. W.; Dudevoir, M. L.; Gopalakrishna, D.; Peters, A. Z.; Heindel, C. C.; Sugimoto, T. J.; Wu, Y.; Lieberman, J. A.; LaMantia, A.-S.

2008-01-01

103

Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.  

PubMed

Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome. PMID:23695276

Vincent, Marie; Collet, Corinne; Verloes, Alain; Lambert, Laetitia; Herlin, Christian; Blanchet, Catherine; Sanchez, Elodie; Drunat, Séverine; Vigneron, Jacqueline; Laplanche, Jean-Louis; Puechberty, Jacques; Sarda, Pierre; Geneviève, David

2014-01-01

104

Chromosome 18q deletion syndrome with autoimmune diabetes mellitus: putative genomic loci for autoimmunity and immunodeficiency.  

PubMed

A girl with 18q deletion syndrome was diagnosed with autoimmune diabetes mellitus and Hashimoto's thyroiditis at the age of 3 yr. In addition, the girl suffered from recurrent infections due to immunoglobulin A and IgG4 deficiency. She was also found to have CD3+CD4+FoxP3+, CD3+CD4+FoxP3+CD25+, and CD3+CD4+CD25+CD127 regulatory T cells deficiency. The exceptional coincidence of the two autoimmune disorders occurring at an early age, and associated with immune deficiency, implies that genes located on deleted 19.4 Mbp region at 18q21.32-q23 (chr18:58,660,699-78,012,870) might play a role in the pathogenesis of autoimmunity leading to ? cell destruction and diabetes. PMID:25403779

Hogendorf, Anna; Lipska-Zietkiewicz, Beata S; Szadkowska, Agnieszka; Borowiec, Maciej; Koczkowska, Magdalena; Trzonkowski, Piotr; Drozdz, Izabela; Wyka, Krystyna; Limon, Janusz; Mlynarski, Wojciech

2014-11-18

105

A Comparative Study of Cognition and Brain Anatomy between Two Neurodevelopmental Disorders: 22q11.2 Deletion Syndrome and Williams Syndrome  

ERIC Educational Resources Information Center

Background: 22q11.2 deletion syndrome (22q11DS) is associated with intellectual disability, poor social interaction and a high prevalence of psychosis. However, to date there have been no studies comparing cognition and neuroanatomical characteristics of 22q11DS with other syndromes to investigate if the cognitive strengths and difficulties and…

Campbell, Linda E.; Stevens, Angela; Daly, Eileen; Toal, Fiona; Azuma, Rayna; Karmiloff-Smith, Annette; Murphy, Declan G. M.; Murphy, Kieran C.

2009-01-01

106

Cognitive-behavioral features of children with Wolf-Hirschhorn syndrome: preliminary report of 12 cases.  

PubMed

As a subset of genetic abnormalities, subtelomeric deletions have been found in 7-10% of individuals with mental retardation (MR). One subtelomeric deletion, Wolf-Hirschhorn syndrome (WHS), causes mild to severe MR, but the cognitive-behavioral features of individuals with WHS have not been studied systematically. To that end, we administered a comprehensive cognitive-behavioral battery to 12 children with WHS, ages 4-17 years, who also had some expressive language. Using the Stanford-Binet (4th Edition), we found cognitive deficits ranged from mild to severe, with mean IQ = 44.1. Interviewing parents with the Vineland Adaptive Behavior Scales, we found mean adaptive behavior score (DQ) = 37.3, with females exhibiting slightly higher scores than males. Cognitive profiles indicated relative strengths in Verbal and Quantitative Reasoning. Adaptive behavior profiles noted significant relative strengths in the Socialization Domain. These cognitive-behavioral profiles differed from children with other subtelomeric deletion syndromes, 2q37 or 8p23. Attention deficits and hyperactivity (ADHD) were observed in 7/12 (58%) of the children we tested. One child attained a score on the Child Autism Rating Scale (CARS) suggestive of mild autism. We conclude that different genetic disorders, which cause MR, produce diverse cognitive-behavioral profiles. Consequently, cognitive-behavioral profiles of children with MR need to be assessed more comprehensively. PMID:18932225

Fisch, Gene S; Battaglia, Agatino; Parrini, Barbara; Youngblom, Janey; Simensen, Richard

2008-11-15

107

Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case.  

PubMed

Contiguous ABCD1 DXS1357E deletion syndrome (CADDS) is a contiguous deletion syndrome involving the ABCD1 and DXS1357E/BAP31 genes on Xq28. Although ABCD1 is responsible for X-linked adrenoleukodystrophy (X-ALD), its phenotype differs from that of CADDS, which manifests with many features of Zellweger syndrome (ZS), including severe growth and developmental retardation, liver dysfunction, cholestasis and early infantile death. We report here the fourth case of CADDS, in which a boy had dysmorphic features, including a flat orbital edge, hypoplastic nose, micrognathia, inguinal hernia, micropenis, cryptorchidism and club feet, all of which are shared by ZS. The patient achieved no developmental milestones and died of pneumonia at 8 months. Biochemical studies demonstrated abnormal metabolism of very long chain fatty acids, which was higher than that seen in X-ALD. Immunocytochemistry and Western blot showed the absence of ALD protein (ALDP) despite the presence of other peroxisomal proteins. Pathological studies disclosed a small brain with hypomyelination and secondary hypoxic-ischemic changes. Neuronal heterotopia in the white matter and leptomeningeal glioneuronal heterotopia indicated a neuronal migration disorder. The liver showed fibrosis and cholestasis. The thymus and adrenal glands were hypoplastic. Array comparative genomic hybridization (CGH) analysis suggested that the deletion was a genomic rearrangement in the 90-kb span starting in DXS1357E/BACP31 exon 4 and included ABCD1, PLXNB3, SRPK3, IDH3G and SSR4, ending in PDZD4 exon 8. Thus, the absence of ALDP, when combined with defects in the B-cell antigen receptor associated protein 31 (BAP31) and other factors, severely affects VLCFA metabolism on peroxisomal functions and produces ZS-like pathology. PMID:22994209

Iwasa, Mitsuaki; Yamagata, Takanori; Mizuguchi, Masashi; Itoh, Masayuki; Matsumoto, Ayumi; Hironaka, Mitsugu; Honda, Ayako; Momoi, Mariko Y; Shimozawa, Nobuyuki

2013-06-01

108

Molecular Screening for 22Q11.2 Deletion Syndrome in Patients With Congenital Heart Disease.  

PubMed

Few studies have investigated the prevalence of 22q11.2 deletion syndrome (22q11.2DS) among patients with isolated heart defects or nonconotruncal heart defects. Polymerase chain reaction (PCR) followed by length polymorphism restriction fragment analysis (RFLP) is useful for low-cost molecular diagnosis and screening. This cross-sectional study included 392 patients with congenital heart disease, described clinical features, and performed PCR-RFLP for analysis of polymorphism in three loci with a high heterozygosity rate located in the typically deleted region of 1.5 megabases. Heterozygosity excluded 22q11.2DS. Patients with homozygosity for the three markers underwent multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) for the final diagnosis, estimating the prevalence of 22q11.2DS. The use of PCR-RFLP excluded 22q11.2DS in 81.6 % (n = 320) of 392 patients. Of the remaining 72 patients, 65 underwent MLPA, showing 22q11.2DS in five cases (prevalence, 1.27 %). Four of these five patients underwent FISH, confirming the MLPA results. All five patients with the deletion had heart diseases commonly found with 22q11.2DS (interrupted aortic arch, persistent truncus arteriosus, tetralogy of Fallot, and ventricular septal defect plus atrial septal defect). Two patients had congenital extracardiac anomaly (one with arched palate and micrognathia and one with hypertelorism). Three patients reported recurrent respiratory infections, and one patient reported hypocalcemia. All were underweight or short in stature for their age. This study contributed to showing the prevalence of 22q11.2DS in patients with any congenital heart disease, with or without other features of the syndrome. Patients with 22q11.2DS may not have all the major features of the syndrome, and those that are found may be due to the heart defect. PMID:24880467

Huber, Janaína; Peres, Vivian Catarino; de Castro, Alexandre Luz; Dos Santos, Tiago Jeronimo; da Fontoura Beltrão, Lauro; de Baumont, Angélica Cerveira; Cossio, Silvia Liliana; Dalberto, Tiago Pires; Riegel, Mariluce; Cañedo, Andrés Delgado; Schaan, Beatriz D'Agord; Pellanda, Lucia Campos

2014-12-01

109

Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects  

PubMed Central

Background 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion. Methods Thirty-two 22q11.2DS subjects among 26 families were enrolled. Results Second generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P?=?0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P?syndrome. PMID:24383682

2014-01-01

110

Functional Gene-Expression Analysis Shows Involvement of Schizophrenia-Relevant Pathways in Patients with 22q11 Deletion Syndrome  

Microsoft Academic Search

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's)

Nico J. M. van Beveren; Lianne C. Krab; Sigrid Swagemakers; Gabriella Buitendijk; Erik Boot; Peter van der Spek; Ype Elgersma; Therese A. M. J. van Amelsvoort

2012-01-01

111

Highly restricted deletion of the SNORD116 region is implicated in Prader-Willi Syndrome.  

PubMed

The SNORD116 locus lies in the 15q11-13 region of paternally expressed genes implicated in Prader-Willi Syndrome (PWS), a complex disease accompanied by obesity and severe neurobehavioural disturbances. Cases of PWS patients with a deletion encompassing the SNORD116 gene cluster, but preserving the expression of flanking genes, have been described. We report a 23-year-old woman who presented clinical criteria of PWS, including the behavioural and nutritional features, obesity, developmental delay and endocrine dysfunctions with hyperghrelinemia. We found a paternally transmitted highly restricted deletion of the SNORD116 gene cluster, the shortest described to date (118?kb). This deletion was also present in the father. This finding in a human case strongly supports the current hypothesis that lack of the paternal SNORD116 gene cluster has a determinant role in the pathogenesis of PWS. Moreover, targeted analysis of the SNORD116 gene cluster, complementary to SNRPN methylation analysis, should be carried out in subjects with a phenotype suggestive of PWS. PMID:24916642

Bieth, Eric; Eddiry, Sanaa; Gaston, Véronique; Lorenzini, Françoise; Buffet, Alexandre; Conte Auriol, Françoise; Molinas, Catherine; Cailley, Dorothée; Rooryck, Caroline; Arveiler, Benoit; Cavaillé, Jérome; Salles, Jean Pierre; Tauber, Maïthé

2015-02-01

112

Hypoplastic left heart syndrome and 21q22.3 deletion.  

PubMed

Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect (CHD), associated with extracardiac anomalies in the 15-28% of cases, in the setting of chromosomal anomalies, mendelian disorders, and organ defects. We report on a syndromic female newborn with HLHS and terminal 21q22.3 deletion (del 21q22.3), investigated by Fluorescence In Situ Hybridization (FISH) using a panel of 26 contiguous BAC probes. Although rare, del 21q22.3 has been described in two additional patients with HLHS. In order to investigate the frequency and role of this chromosomal imbalance in the pathogenesis of left-sided obstructive heart defects, we screened for del 21q22.3 a series of syndromic and non-syndromic children with HLHS, aortic coarctation and valvular aortic stenosis, consecutively admitted to our hospital in a three-year period. Although none of the 56 analyzed patients were hemizygous for this region, the present case report and published patients argue that del 21q22 should be added to the list of chromosomal imbalances associated with HLHS. Accordingly, the presence of a cardiac locus mapping in the critical region cannot be excluded. © 2015 Wiley Periodicals, Inc. PMID:25663264

Ciocca, Laura; Digilio, M Cristina; Lombardo, Antonietta; D'Elia, Gemma; Baban, Anwar; Capolino, Rossella; Petrocchi, Stefano; Russo, Serena; Sirleto, Pietro; Roberti, M Cristina; Marino, Bruno; Angioni, Adriano; Dallapiccola, Bruno

2015-03-01

113

7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover  

SciTech Connect

Williams syndrome (WS) is a multisystem disorder characterized by mental retardation, a specific neurobehavioral profile, characteristic facies, infantile hypercalcemia, cardiovascular abnormalities, progressive joint limitation, hermas, and soft skin. Recent studies have shown that hemizygosity at the elastin (ELN) gene locus on chromosome 7q is associated with WS. Furthermore, two FISH studies using cosmid recombinants containing the 5{prime} or the 3{prime} end of the ELN gene revealed deletion of the entire ELN gene in 90%-96% of classical WS cases. However, the size of the 7q11.23 deletions and the mechanism by which these deletions arise are not known. 15 refs., 2 figs., 1 tab.

Urban, Z.; Csiszar, K.; Boyd, C.D. [and others

1996-10-01

114

FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome.  

PubMed

We describe a patient with autism and brachymetaphalangy, meeting criteria for 2q37 deletion syndrome (also called Albright Hereditary Osteodystrophy-like syndrome or Brachydactyly-Mental Retardation syndrome, OMIM 600430). Our molecular cytogenetic studies, including array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH), define the extent of the de novo deletion to a 3.5 Mb region on 2q37.3. Although a number of reports of patients with 2q37 deletion syndrome have been published, it remains unclear if gene expression and/or translation are altered by the deletion, thus contributing to the observed phenotypes. To address this question, we selected several candidate genes for the neuropsychiatric and skeletal anomalies found in this patient (autism and brachymetaphalangy). The deleted region in 2q37.3 includes the FERM, RhoGEF and pleckstrin domain protein 2 (FARP2), glypican 1 (GPC1), vigilin (HDLBP), kinesin family member 1A (KIF1A) and proline-alanine-rich STE20-related kinase (PASK), all of which are involved in skeletal or neural differentiation processes. Expression analyses of these genes were performed using RNA from lymphoblastoid cell lines of the patient and his family members. Here we demonstrate that three of these genes, FARP2, HDLBP, and PASK, are considerably downregulated in the patient's cell line. We hypothesize that haploinsufficiency of these genes may have contributed to the patient's clinical phenotype. PMID:19365831

Felder, Bärbel; Radlwimmer, Bernhard; Benner, Axel; Mincheva, Antoaneta; Tödt, Grischa; Beyer, Kim S; Schuster, Claudia; Bölte, Sven; Schmötzer, Gabriele; Klauck, Sabine M; Poustka, Fritz; Lichter, Peter; Poustka, Annemarie

2009-05-01

115

A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5  

PubMed Central

Background Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Case presentation Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. Conclusion The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed. PMID:24517234

2014-01-01

116

Deletion of small nuclear ribonucleoprotein polypeptide N (SNRPN) in Prader-Willi syndrome detected by fluorescence in situ hybridization: Two sibs with the typical phenotype without a cytogenetic deletion in chromosome 15q  

SciTech Connect

The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene is regarded as one of the candidates for Prader-Willi syndrome (PWS). We describe two sibs with typical PWS presenting deletion of SNRPN detected by fluorescence in situ hybridization (FISH). Neither a cytogenetically detectable 15q12 deletion nor a deletion for the D15S11, D15S10, and GABRB3 cosmid probes were found in either patient. This implies a smaller deletion limited to the PWS critical region. FISH with a SNRPN probe will permit analysis of PWS patients with limited deletions not detectable with other probes. 22 refs., 1 fig.

Ishikawa, Tatsuya; Kibe, Tetsuya; Wada, Yoshiro [Nagoya City Univ. Medical School (Japan)] [Nagoya City Univ. Medical School (Japan)

1996-04-24

117

Occurrence of the alpha thalassaemia-mental retardation syndrome (non-deletional type) in an Australian male.  

PubMed

The rare association of alpha thalassaemia and mental retardation has been described previously. Molecular studies of the alpha globin cluster in these cases have been heterogeneous, with some patients having large deletions while in others the alpha globin complex appears to be intact (non-deletional). The non-deletional cases form a distinct group whose features include severe mental retardation, haematological changes of haemoglobin H (Hb H) disease, developmental defects, and unusual patterns of inheritance. To date, five cases have been described with non-deletional alpha thalassaemia-mental retardation. We present here a further example of a young male of Northern European origin who appears to have the non-deletional form of the disease. Clinical features included severe mental retardation, Hb H disease, and developmental defects similar to those reported previously. DNA mapping, including pulsed field electrophoresis, showed no evidence of deletions within the alpha globin cluster. Karyotypic analysis indicated an increase in random breakage, which has been observed previously in one case of deletional alpha thalassaemia-mental retardation. Profuse Hb H bodies and Hb H on electrophoresis were consistent with Hb H disease. However, the latter was present at a relatively low level (1.6%) and, as well, the mean corpuscular volume (82.8 fl) and mean corpuscular haemoglobin (26.4 pg) were surprisingly high. Our findings are compared to other cases described with the non-deletional Hb H-mental retardation syndrome. PMID:2231651

Harvey, M P; Kearney, A; Smith, A; Trent, R J

1990-09-01

118

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge\\/velo-cardio-facial syndrome  

Microsoft Academic Search

Deletions of chromosome 22q11.2 have been associated with distinct phenotypes including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These diseases result from a failure to form derivatives of the third and fourth branchial arches during development. DGS\\/VCFS deletions usually encompass about 3 Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies have failed to demonstrate

Francesca Amati; Emanuela Conti; Antonio Novelli; Mario Bengala; Maria Cristina Digilio; Bruno Marino; Aldo Giannotti; Orazio Gabrielli; Giuseppe Novelli; Bruno Dallapiccola

1999-01-01

119

Two Cases of Chromosome 22q11.2 Deletion Syndrome Diagnosed in 12-Year-Old Boys with Hypocalcemic Seizures  

PubMed Central

Chromosome 22q11.2 deletion syndrome is the most common interstitial deletion syndrome. Major clinical manifestation includes hypocalcemia secondary to hypoparathyroidim. At least 10% of the patients with this syndrome had hypocalcemic seizures which are generally improved over the first year of life because of the increase of parathyroid gland hypertrophy and dietary calcium intake. We present two cases of this syndrome diagnosed in 12-year-old boys with new onset hypocalcemic seizures. This case report hopes to call attention to this syndrome as a potential cause of hypocalcemic seizures even after the neonatal period. Furthermore, our first patient showed inheritance from a paternal deletion which is not as common as maternal deletions. This is the first case report of hypocalcemic seizure with a paternally inherited 22q11.2 deletion in Korea. PMID:24649462

Hyun, Jae Won; Chung, Hwa Kyoung; Kim, Sung-Hee; Choi, Ye Ji; Kim, Sung Jin; Kim, Hae Soon; Lee, Hyang Woon

2012-01-01

120

Cri du chat syndrome determined by the 5p15.3?pter deletion—diagnostic problems  

Microsoft Academic Search

A cytogenetic analysis was performed on an 8-day-old girl, who was suspected of Cri du chat syndrome (CdCS) on the basis of a cat-like cry, despite her dysmorphic features not being characteristic of this syndrome. The cytogenetic analysis revealed a partial deletion of the short arm of chromosome 5, but did not allow precise specification of the break points. Fluorescence

Izabela Laczmanska; Agnieszka Stembalska; Justyna Gil; Halina Czemarmazowicz; Maria Sasiadek

2006-01-01

121

Psychiatric Disorders From Childhood to Adulthood in 22q11.2 Deletion Syndrome: Results From the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome  

PubMed Central

Objective Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome. PMID:24577245

Schneider, Maude; Debbané, Martin; Bassett, Anne S.; Chow, Eva W.C.; Fung, Wai Lun Alan; van den Bree, Marianne B.M.; Owen, Michael; Murphy, Kieran C.; Niarchou, Maria; Kates, Wendy R.; Antshel, Kevin M.; Fremont, Wanda; McDonald-McGinn, Donna M.; Gur, Raquel E.; Zackai, Elaine H.; Vorstman, Jacob; Duijff, Sasja N.; Klaassen, Petra W.J.; Swillen, Ann; Gothelf, Doron; Green, Tamar; Weizman, Abraham; Van Amelsvoort, Therese; Evers, Laurens; Boot, Erik; Shashi, Vandana; Hooper, Stephen R.; Bearden, Carrie E.; Jalbrzikowski, Maria; Armando, Marco; Vicari, Stefano; Murphy, Declan G.; Ousley, Opal; Campbell, Linda E.; Simon, Tony J.; Eliez, Stephan

2014-01-01

122

Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients  

SciTech Connect

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11{minus}q13. Approximately 70% of these patients have a large deletion of {approximately}4 Mb extending from D15S9 (ML34) through D15S12 (IR10A). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated for YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of these markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542. 46 refs., 2 figs., 3 tabs.

Christian, S.L.; Huang, B.; Ledbetter, D.H. [National Institutes of Health, Bethesda, MD (United States)] [and others

1995-07-01

123

A Longitudinal Examination of the Psychoeducational, Neurocognitive, and Psychiatric Functioning in Children with 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnesses appearing in late adolescence/early adulthood. Little is known of the developmental…

Hooper, Stephen R.; Curtiss, Kathleen; Schoch, Kelly; Keshavan, Matcheri S.; Allen, Andrew; Shashi, Vandana

2013-01-01

124

Social Skills and Associated Psychopathology in Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Interventions  

ERIC Educational Resources Information Center

Background: Although distinctive neuropsychological impairments have been delineated in children with chromosome 22q11 deletion syndrome (22q11DS), social skills and social cognition remain less well-characterised. Objective: To examine social skills and social cognition and their relationship with neuropsychological function/behaviour and…

Shashi, V.; Veerapandiyan, A.; Schoch, K.; Kwapil, T.; Keshavan, M.; Ip, E.; Hooper, S.

2012-01-01

125

Maladaptive Conflict Monitoring as Evidence for Executive Dysfunction in Children with Chromosome 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

Using an adaptation of the Attentional Networks Test, we investigated aspects of executive control in children with chromosome 22q11.2 deletion syndrome (DS22q11.2), a common but not well understood disorder that produces non-verbal cognitive deficits and a marked incidence of psychopathology. The data revealed that children with DS22q11.2…

Bish, Joel P.; Ferrante, Samantha M.; McDonald-McGinn, Donna; Zackai, Elaine; Simon, Tony J.

2005-01-01

126

Mosaic Chromosome 18q Partial Deletion Syndrome with Bilateral Full-thickness Corneal Disease: Surgical Intervention and Histopathology.  

PubMed

Abstract A 2-month-old boy diagnosed with a mosaic chromosome 18q partial deletion syndrome was referred for bilateral cloudy corneas. The abnormal metaphases had a terminal deletion of the long arm of chromosome 18 as clonal abnormality. The cytogenetics findings were 46,XY, del (18)(q21.2)[12]/46,XY[20]. Ocular findings included bilateral microcornea with dense opacification and unilateral iris and chorioretinal coloboma. Penetrating keratoplasty (PK) was performed on both eyes. Histopathology of the host corneal button showed complete loss of Bowman's layer, hyperkeratosis of the epithelium, stromal neovascularization, and leukocyte infiltration. Descemet's membrane and endothelium were irregular in both specimens. CD45 stain for leukocytes confirmed perivascular and epithelial leukocytes infiltration. Mosaic chromosome 18q deletion syndrome is a rare genetic abnormality with a variable phenotype - including ocular findings - and hence, warrants an ophthalmic evaluation and genetic counseling. PMID:24024746

Galvin, Jennifer A; LeBoyer, Russell M; Michelotti, Monica; Monte, Monte A Del; Elner, Victor M; Mian, Shazad I

2015-03-01

127

Movement disorders and other motor abnormalities in adults with 22q11.2 deletion syndrome.  

PubMed

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice. © 2015 Wiley Periodicals, Inc. PMID:25684639

Boot, Erik; Butcher, Nancy J; van Amelsvoort, Thérèse Amj; Lang, Anthony E; Marras, Connie; Pondal, Margarita; Andrade, Danielle M; Fung, Wai Lun Alan; Bassett, Anne S

2015-03-01

128

Complex structural rearrangement features suggesting chromoanagenesis mechanism in a case of 1p36 deletion syndrome.  

PubMed

Genome rearrangements are caused by the erroneous repair of DNA double-strand breaks, leading to several alterations that result in loss or gain of the structural genomic of a dosage-sensitive genes. However, the mechanisms that promote the complexity of rearrangements of congenital or developmental defects in human disease are unclear. The investigation of complex genomic abnormalities could help to elucidate the mechanisms and causes for the formation and facilitate the understanding of congenital or developmental defects in human disease. We here report one case of a patient with atypical clinical features of the 1p36 syndrome and the use of cytogenomic techniques to characterize the genomic alterations. Analysis by multiplex ligation-dependent probe amplification and array revealed a complex rearrangement in the 1p36.3 region with deletions and duplication interspaced by normal sequences. We also suggest that chromoanagenesis could be a possible mechanism involved in the repair and stabilization of this rearrangement. PMID:24985706

Zanardo, Évelin Aline; Piazzon, Flavia Balbo; Dutra, Roberta Lelis; Dias, Alexandre Torchio; Montenegro, Marília Moreira; Novo-Filho, Gil Monteiro; Costa, Thaís Virgínia Moura Machado; Nascimento, Amom Mendes; Kim, Chong Ae; Kulikowski, Leslie Domenici

2014-12-01

129

Terminal deletion 2q37.3 in a patient with Klippel-Trenaunay-Weber syndrome.  

PubMed

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disorder, characterized by capillary, venous and lymphatic vascular malformations in association with bone and soft tissue hypertrophy. We report a KTWS patient with extensive hemangiomatosis of the right lower limb, trunk and upper limbs; bone and soft tissue hypertrophy of upper limbs, scapular girdle and right lower limb; and muscle atrophy on left lower limb with marked body asymmetry, scoliosis and toe malformations. These pathological features are associated with moderate mental retardation, mild renal and hepatic abnormalities. We identified by array CGH (Comparative Genomic Hybridization) a submicroscopic deletion 2q37.3 that could be related to impaired cognitive function. To our knowledge this is the first reported 2q37.3 microdeletion in a patient with KTWS. PMID:23438794

Puiu, Ileana; Stoica, Alin; Sosoi, Simona; Puiu, Alexandra; Ioana, Mihai; Burada, Florin

2013-10-01

130

Spontaneous deletion in the FMR-1 gene in a patient with fragile X syndrome and cherubism  

SciTech Connect

Fragile X mental retardation results from the transcriptional inactivation of the FMR-1 gene and is commonly caused by the expansion of an unstable CGG trinucleotide repeat located in the first exon of the FMR-1 gene. We describe here a two generation fragile X family in which expansion of the CGG repeat may have resulted in a deletion of a least portion of the FMR-1 gene. One member of this family, AB, carries an apparent deletion of the FMR-1 gene and presents with mental retardation and also cherubism, a feature not usually associated with fragile X syndrome. Cherubism is a condition characterized by a swelling of the lower face and is caused by giant cell lesions of the mandible and maxilla, and often the anterior ends of the ribs. The size of the CGG repeat region in this family was determined by Southern analysis of BglII, EcoRI, and PstI digested genomic DNA, isolated from peripheral blood lymphocytes, using a 558 bp PstI-Xhol fragment specific for the 5{prime}-end of the FMR-1 gene. SB and TB, the mother and maternal half-brother of AB, respectively, were both found to carry an expanded FMR-1 allele with greater than 200 CGG repeats. Negligible hybridization was observed in the DNA of AB. In addition, no amplification was observed when the polymerase chain reaction (PCR) was performed using primers flanking the CGG repeat region. These results are consistent with a deletion of at least the 5{prime} portion of the FMR-1 gene in the majority of peripheral blood lymphocytes. Further work is underway using FMR-1 cDNA probes and additional PCR primers to determine the nature of the molecular lesion in AB`s DNA and determine the relationship of this lesion to his cherubism.

Popovich, B.W.; Anoe, K.S.; Johnson, D.B. [Oregon Health Sciences Univ., Portland, OR (United States)] [and others

1994-09-01

131

Prodromal Symptoms in Adolescents with 22q11.2 Deletion Syndrome and Schizotypal Personality Disorder  

PubMed Central

Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research on the manifestation of these symptoms in 22q11.2DS patients, and no studies of differences in prodromal symptom patterns between genetically and behaviorally defined at-risk groups. In this study, demographically-matched groups of 23 SPD, 23 22q11.2DS, and 23 control participants were administered the Structured Interview for Prodromal Syndromes (SIPS). Both risk groups showed elevated positive, negative, disorganized, and general prodromal symptoms, as well as elevations on 10 of the same individual symptom items, relative to the control group. Approximately 60% of individuals in the 22q11.2DS group and 70% of individuals in the SPD group met symptom criteria for a prodromal psychosis syndrome. The 22q11.2DS group scored significantly higher than the SPD group on the “decreased ideational richness” item and showed a trend toward greater motor abnormalities. The results suggest that these two high-risk groups are similar in prodromal symptom presentation, possibly as a result of overlapping causal mechanisms, and that standardized measures of prodromal syndromes like the SIPS can be used to identify 22q11.2DS patients at greatest risk for conversion to psychosis. PMID:21507614

Shapiro, DI; Cubells, JF; Ousley, OY; Rockers, K; Walker, EF

2011-01-01

132

Prodromal symptoms in adolescents with 22q11.2 deletion syndrome and schizotypal personality disorder.  

PubMed

Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research on the manifestation of these symptoms in 22q11.2DS patients, and no studies of differences in prodromal symptom patterns between genetically and behaviorally defined at-risk groups. In this study, demographically matched groups of 23 SPD, 23 22q11.2DS, and 23 control participants were administered the Structured Interview for Prodromal Syndromes (SIPS). Both risk groups showed elevated positive, negative, disorganized, and general prodromal symptoms, as well as elevations on 10 of the same individual symptom items, relative to the control group. Approximately 60% of individuals in the 22q11.2DS group and 70% of individuals in the SPD group met symptom criteria for a prodromal psychosis syndrome. The 22q11.2DS group scored significantly higher than the SPD group on the "decreased ideational richness" item and showed a trend toward greater motor abnormalities. The results suggest that these two high-risk groups are similar in prodromal symptom presentation, possibly as a result of overlapping causal mechanisms, and that standardized measures of prodromal syndromes like the SIPS can be used to identify 22q11.2DS patients at greatest risk for conversion to psychosis. PMID:21507614

Shapiro, D I; Cubells, J F; Ousley, O Y; Rockers, K; Walker, E F

2011-06-01

133

Psychopathology and cognition in children with 22q11.2 deletion syndrome  

PubMed Central

Background Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems. Aims To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children’s intellectual impairment. Method Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0). Results More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (P<0.001) and showed a range of neurocognitive impairments. Increased risk of psychopathology was not mediated by intellectual impairment. Conclusions 22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment. PMID:24115343

Niarchou, Maria; Zammit, Stanley; van Goozen, Stephanie H. M.; Thapar, Anita; Tierling, Hayley M.; Owen, Michael J.; van den Bree, Marianne B. M.

2014-01-01

134

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers  

PubMed Central

INTRODUCTION: Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis, mental retardation, overfriendliness, and ocular and renal abnormalities comprise typical symptoms in WBS. Although fluorescence in situ hybridization is widely used for diagnostic confirmation, microsatellite DNA markers are considered highly informative and easily manageable. OBJECTIVES: This study aimed to test the microsatellite markers for the diagnosis of Williams-Beuren syndrome, to determine the size and parental origin of microdeletion, compare the clinical characteristics between patients with different sizes of the deletion and parental origin. METHODS: We studied 97 patients with clinical diagnosis of Williams-Beuren syndrome using five microsatellite markers: D7S1870, D7S489, D7S613, D7S2476 and D7S489_A. RESULTS AND DISCUSSION: Using five markers together, the result was informative in all patients. The most informative marker was D7S1870 (78.4%), followed by D7S613 (75.3%), D7S489 (70.1%) and D7S2476 (62.9%). The microdeletion was present in 84 (86.6%) patients and absent in 13 (13.4%) patients. Maternal deletions were found in 52.4% of patients and paternal deletions in 47.6% of patients. The observed size of deletions was 1.55 Mb in 76/84 patients (90.5%) and 1.84 Mb in 8/84 patients (9.5%). SVAS as well as ocular and urinary abnormalities were more frequent in the patients with a deletion. There were no clinical differences in relation to either the size or parental origin of the deletion. CONCLUSION: Using these five selected microsatellite markers was informative in all patients, thus can be considered an alternative method for molecular diagnosis in Williams-Beuren syndrome. PMID:21808859

Dutra, Roberta Lelis; de Campos Pieri, Patrícia; Teixeira, Ana Carolina Dias; Honjo, Rachel Sayuri; Bertola, Debora Romeo; Kim, Chong Ae

2011-01-01

135

Neuroanatomic Predictors to Prodromal Psychosis in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome): A Longitudinal Study  

PubMed Central

Background Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest. Methods We acquired high-resolution anatomic MR images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings and 24 age-matched community controls at two timepoints, between late childhood (mean age, 11.9 years) and mid-adolescence (mean age, 15.1 years). Results With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community controls during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p < .002) and verbal IQ (p < .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2. Conclusions These findings are in line with studies of non-VCFS individuals at risk for schizophrenia, and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS. PMID:21195387

Kates, Wendy R.; Antshel, Kevin M.; Faraone, Stephen V.; Fremont, Wanda P.; Higgins, Anne Marie; Shprintzen, Robert J.; Botti, Jo-Anna; Kelchner, Lauren; McCarthy, Christopher

2010-01-01

136

An atypical deletion of the Williams–Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism  

PubMed Central

Background During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive–behavioural profile (CBP) associated with Williams–Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non?social anxiety and language delay. Methods Using array?based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11?89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. Results The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4–3.1?Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic ?1.5?Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare ?1.84?Mb WBS deletion. Conclusion Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci. PMID:16971481

Edelmann, Lisa; Prosnitz, Aaron; Pardo, Sherly; Bhatt, Jahnavi; Cohen, Ninette; Lauriat, Tara; Ouchanov, Leonid; González, Patricia J; Manghi, Elina R; Bondy, Pamela; Esquivel, Marcela; Monge, Silvia; Delgado, Marietha F; Splendore, Alessandra; Francke, Uta; Burton, Barbara K; McInnes, L Alison

2007-01-01

137

A novel homozygous 10 nucleotide deletion in BBS10 causes Bardet-Biedl syndrome in a Pakistani family.  

PubMed

Bardet-Biedl Syndrome is a multisystem autosomal recessive disorder characterized by central obesity, polydactyly, hypogonadism, learning difficulties, rod-cone dystrophy and renal dysplasia. Bardet-Biedl Syndrome has a prevalence rate ranging from 1 in 100,000 to 1 in 160,000 births although there are communities where Bardet-Biedl Syndrome is found at a higher frequency due to consanguinity. We report here a Pakistani consanguineous family with two affected sons with typical clinical features of Bardet-Biedl Syndrome, in addition to abnormal liver functioning and bilateral basal ganglia calcification, the latter feature being typical of Fahr's disease. Homozygous regions obtained from SNP array depicted three known genes BBS10, BBS14 and BBS2. Bidirectional sequencing of all coding exons by traditional sequencing of all these three genes showed a homozygous deletion of 10 nucleotides (c.1958_1967del), in BBS10 in both affected brothers. The segregation analysis revealed that the parents, paternal grandfather, maternal grandmother and an unaffected sister were heterozygous for the deletion. Such a large deletion in BBS10 has not been reported previously in any population and is likely to be contributing to the phenotype of Bardet-Biedl Syndrome in this family. PMID:23403234

Agha, Zehra; Iqbal, Zafar; Azam, Maleeha; Hoefsloot, Lies H; van Bokhoven, Hans; Qamar, Raheel

2013-04-25

138

Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)  

SciTech Connect

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65% brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter. 42 refs., 2 figs., 3 tabs.

Greenberg, F.; Lewis, R.A.; Potocki, L. [Baylor College of Medicine, Houston, TX (United States)] [and others] [Baylor College of Medicine, Houston, TX (United States); and others

1996-03-29

139

Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth.  

PubMed Central

Williams syndrome (WS) is a developmental disorder with variable phenotypic expression associated, in most cases, with a hemizygous deletion of part of chromosomal band 7q11.23 that includes the elastin gene (ELN). We have investigated the frequency and size of the deletions, determined the parental origin, and correlated the molecular results with the clinical findings in 65 WS patients. Hemizygosity at the ELN locus was established by typing of two intragenic polymorphisms, quantitative Southern analysis, and/or FISH. Polymorphic markers covering the deletion and flanking regions were ordered by a combination of genetic and physical mapping. Genotyping of WS patients and available parents for 13 polymorphisms revealed that of 65 clinically defined WS patients, 61 (94%) had a deletion of the ELN locus and were also hemizygous (or noninformative) at loci D7S489B, D7S2476, D7S613, D7S2472, and D7S1870. None of the four patients without ELN deletion was hemizygous at any of the polymorphic loci studied. All patients were heterozygous (or noninformative) for centromeric (D7S1816, D7S1483, and D7S653) and telomeric (D7S489A, D7S675, and D7S669) flanking loci. The genetic distance between the most-centromeric deleted locus, D7S489B, and the most-telomeric one, D7S1870, is 2 cM. The breakpoints cluster at approximately 1 cM to either side of ELN. In 39 families informative for parental origin, all deletions were de novo, and 18 were paternally and 21 maternally derived. Comparison of clinical data, collected in a standardized quantifiable format, revealed significantly more severe growth retardation and microcephaly in the maternal deletion group. An imprinted locus, silent on the paternal chromosome and contributing to statural growth, may be affected by the deletion. Images Figure 1 Figure 4 PMID:8808592

Pérez Jurado, L. A.; Peoples, R.; Kaplan, P.; Hamel, B. C.; Francke, U.

1996-01-01

140

Matriptase Deletion Initiates a Sjögren’s Syndrome-Like Disease in Mice  

PubMed Central

Objective The objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model. Methods Embryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers. Results Embryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjögren’s syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjögren’s syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers. Conclusions Our findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland dysfunction in the absence of inflammation while systemic deletion can induce a primary Sjögren’s syndrome like phenotype with autoimmunity and loss of gland function. PMID:24551030

Liu, Xibao; Swaim, William D.; Lai, Zhennan; Cabrera-Perez, Javier; Di Pasquale, Giovanni; Ambudkar, Indu S.; Bugge, Thomas H.; Chiorini, John A.

2014-01-01

141

Decreased DGCR8 Expression and miRNA Dysregulation in Individuals with 22q11.2 Deletion Syndrome  

PubMed Central

Deletion of the 1.5–3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70–80%), hypocalcemia (20–60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS. PMID:25084529

Sellier, Chantal; Hwang, Vicki J.; Dandekar, Ravi; Durbin-Johnson, Blythe; Charlet-Berguerand, Nicolas; Ander, Bradley P.; Sharp, Frank R.; Angkustsiri, Kathleen; Simon, Tony J.; Tassone, Flora

2014-01-01

142

Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy  

PubMed Central

Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM. PMID:23768516

Arndt, Anne-Karin; Schafer, Sebastian; Drenckhahn, Jorg-Detlef; Sabeh, M. Khaled; Plovie, Eva R.; Caliebe, Almuth; Klopocki, Eva; Musso, Gabriel; Werdich, Andreas A.; Kalwa, Hermann; Heinig, Matthias; Padera, Robert F.; Wassilew, Katharina; Bluhm, Julia; Harnack, Christine; Martitz, Janine; Barton, Paul J.; Greutmann, Matthias; Berger, Felix; Hubner, Norbert; Siebert, Reiner; Kramer, Hans-Heiner; Cook, Stuart A.; MacRae, Calum A.; Klaassen, Sabine

2013-01-01

143

Wilms' tumor and gonadal dysgenesis in a child with the 2q37.1 deletion syndrome.  

PubMed

Here we report Wilms' tumor, gonadal dysgenesis and a bifid uterus in an 18-month-old female with a terminal deletion of the long arm of chromosome 2 [46,XX,del(2)(q37.1)]. Since Wilms' tumor has been previously reported in the 2q37 deletion syndrome, the present observation raises the question of whether a tumor susceptibility gene maps to chromosome 2q37 and suggests giving consideration to the possible occurrence of Wilms' tumor in the course of disease. PMID:9650765

Viot-Szoboszlai, G; Amiel, J; Doz, F; Prieur, M; Couturier, J; Zucker, J N; Henry, I; Munnich, A; Vekemans, M; Lyonnet, S

1998-04-01

144

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome.  

PubMed

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5'-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons. PMID:24549057

Bertelsen, Birgitte; Melchior, Linea; Jensen, Lars R; Groth, Camilla; Glenthøj, Birte; Rizzo, Renata; Debes, Nanette Mol; Skov, Liselotte; Brøndum-Nielsen, Karen; Paschou, Peristera; Silahtaroglu, Asli; Tümer, Zeynep

2014-11-01

145

A deletion mutation in the 3' end of the alpha 5(IV) collagen gene in juvenile-onset Alport syndrome.  

PubMed

Alport syndrome is a hereditary progressive glomerular basement membrane disorder in which juvenile-or adult-onset renal failure is often accompanied by sensorineural deafness and ocular abnormalities. Recently, mutations have been found in the type IV collagen alpha 5 chain gene in patients with X-linked Alport syndrome. This study searched for gene mutations in seven unrelated Japanese patients by the use of conventional Southern blot analysis with cDNA probes for the carboxyl-terminal noncollagenous domain that is encoded by exons 46 to 51. A deletion mutation was found in a patient who developed juvenile-onset (age 15) ESRD with typical ultrastructural glomerular basement membrane destruction and sensorineural hearing loss but no characteristic ocular abnormalities. His mother showed hematuria and proteinuria with normal renal function, suggesting that she may be the heterozygous carrier. Exon-specific polymerase chain reaction amplified the coding sequence of exon 48 but not exons 49 to 51. Analysis with pulsed-field gel electrophoresis revealed that the deletion is approximately 10 kb in length and does not involve the CpG island, which is located in the 3' distal site of the gene. Identification of this novel deletion causing juvenile-type Alport syndrome would contribute to elucidating the mechanisms of renal failure progression in the syndrome. PMID:8011973

Saito, A; Sakatsume, M; Yamazaki, H; Ogata, F; Hirasawa, Y; Arakawa, M

1994-03-01

146

Deletions of the elastin gene at 7q11.23 occur in {approximately}90% of patients with Williams syndrome  

SciTech Connect

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5{prime} or the 3{prime} end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA){sub n} repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis. 25 refs., 3 figs., 1 tab.

Nickerson, E.; Greenberg, F.; McCaskill, C.; Shaffer, L.G. [Baylor College of Medicine, Houston, TX (United States); Keating, M.T. [Univ. of Utah, Salt Lake City (United States)

1995-05-01

147

Lynch-like syndrome: Characterization and comparison with EPCAM deletion carriers.  

PubMed

Colorectal cancers (CRCs) with microsatellite instability-high (MSI+) but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch-like syndrome (LLS). The underlying mechanism and clinical significances of LLS are largely unknown. We measured MSI and MMR protein expression in 4,765 consecutive CRC cases. Among these, MSI+ cases were further classified based on clinical parameters, germline sequencing of MMR genes or polymerase ? (POLE) and ? (POLD1) and promoter methylation analysis of MLH1 and MSH2. We found that MSI+ and MMR protein-deficient CRCs comprised 6.3% (N?=?302) of this cohort. On the basis of germline sequencing of 124 cases, we identified 54 LS with MMR germline mutation (LS-MMR), 15 LS with EPCAM deletions (LS-EPCAM) and 55 LLS patients. Of the 55 LLS patients, six (10.9%) had variants of unknown significance in the genes tested, and one patient had a novel somatic mutation (p.S459P) in POLE. In patients with biallelic deletions of EPCAM, all tumors and their matched normal mucosa showed promoter hypermethylation of MSH2. Finally, we found that patients with LLS and LS-EPCAM shared clinical features that differed from LS-MMR patients, including lower frequency of fulfillment of the revised Bethesda guidelines (83.6 and 86.7% vs. 98.1% for LS-MMR) and older mean age at CRC diagnosis (52.6 and 52.7 years vs. 43.9 years for LS-MMR). We identified somatic mutation in POLE as a rare underlying cause for MMR deficiency in LLS. The similarity between LLS and LS-EPCAM suggests LLS as a subset of familial MSI+ CRC. PMID:25110875

Kang, So Young; Park, Cheol Keun; Chang, Dong Kyung; Kim, Jong Won; Son, Hee Jung; Cho, Yong Beom; Yun, Seong Hyeon; Kim, Hee Cheol; Kwon, Moosik; Kim, Kyoung-Mee

2015-04-01

148

The development of cognitive control in children with chromosome 22q11.2 deletion syndrome  

PubMed Central

Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD) were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT), a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ). When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures. PMID:24959159

Shapiro, Heather M.; Tassone, Flora; Choudhary, Nimrah S.; Simon, Tony J.

2014-01-01

149

Deficits in mental state attributions in individuals with 22q11.2 deletion syndrome (velo-cardio-facial syndrome).  

PubMed

Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites University of California, Los Angeles (UCLA) and State University of New York (SUNY) Upstate Medical University. The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e. mentalizing) and Appropriateness. Using Repeated Measures analysis of variance (ANOVA), we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions. PMID:22962003

Ho, Jennifer S; Radoeva, Petya D; Jalbrzikowski, Maria; Chow, Carolyn; Hopkins, Jessica; Tran, Wen-Ching; Mehta, Ami; Enrique, Nicole; Gilbert, Chelsea; Antshel, Kevin M; Fremont, Wanda; Kates, Wendy R; Bearden, Carrie E

2012-12-01

150

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome  

PubMed Central

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS. PMID:21779178

Beri, Silvana; De Agostini, Cristina; Novara, Francesca; Fichera, Marco; Grillo, Lucia; Galesi, Ornella; Vetro, Annalisa; Ciccone, Roberto; Bonati, Maria Teresa; Giglio, Sabrina; Guerrini, Renzo; Osimani, Sara; Marelli, Susan; Zucca, Claudio; Grasso, Rita; Borgatti, Renato; Mani, Elisa; Motta, Cristina; Molteni, Massimo; Romano, Corrado; Greco, Donatella; Reitano, Santina; Baroncini, Anna; Lapi, Elisabetta; Cecconi, Antonella; Arrigo, Giulia; Patricelli, Maria Grazia; Pantaleoni, Chiara; D'Arrigo, Stefano; Riva, Daria; Sciacca, Francesca; Dalla Bernardina, Bernardo; Zoccante, Leonardo; Darra, Francesca; Termine, Cristiano; Maserati, Emanuela; Bigoni, Stefania; Priolo, Emanuela; Bottani, Armand; Gimelli, Stefania; Bena, Frederique; Brusco, Alfredo; di Gregorio, Eleonora; Bagnasco, Irene; Giussani, Ursula; Nitsch, Lucio; Politi, Pierluigi; Martinez-Frias, Maria Luisa; Martínez-Fernández, Maria Luisa; Martínez Guardia, Nieves; Bremer, Anna; Anderlid, Britt-Marie; Zuffardi, Orsetta

2011-01-01

151

Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.  

PubMed

Kabuki syndrome (KS) is a rare genetic disease that causes developmental delay and congenital anomalies. Since the identification of MLL2 mutations as the primary cause of KS, such mutations have been identified in 56%-76% of affected individuals, suggesting that there may be additional genes associated with KS. Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. Although KDM6A escapes X inactivation, we found a skewed X inactivation pattern, in which the deleted X chromosome was inactivated in the majority of the cells. This study identifies KDM6A mutations as another cause of KS and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes. PMID:22197486

Lederer, Damien; Grisart, Bernard; Digilio, Maria Cristina; Benoit, Valérie; Crespin, Marianne; Ghariani, Sophie Claire; Maystadt, Isabelle; Dallapiccola, Bruno; Verellen-Dumoulin, Christine

2012-01-13

152

Prevalence of hypocalcaemia and its associated features in 22q11·2 deletion syndrome  

PubMed Central

Summary Background 22q11·2 deletion syndrome (22q11·2DS) is a relatively common yet under-recognized genetic syndrome that may present with endocrine features. We aimed to address the factors that contribute to the high prevalence of hypocalcaemia. Methods We investigated hypocalcaemia in a well-characterized sample of 138 adults with 22q11·2DS (65 m, 73 F; mean age 34·2, SD 11·8, years) using laboratory studies and lifelong medical records. Logistic regression modelling was used to identify features associated with lifetime prevalence of hypocalcaemia. Results Of the total sample, 111 (80·4%) had a lifetime history of hypocalcaemia. Eleven (84·6%) of 13 subjects with neonatal hypocalcaemia had documented recurrence of hypocalcaemia. Lifetime history of hypocalcaemia was associated with lifetime prevalence of hypoparathyroidism (P < 0·0001) and hypothyroidism (P = 0·04), as statistically independent factors. Hypomagnesaemia was associated with concurrent hypocalcaemic measurements, especially in the presence of concurrent hypoparathyroidism (P = 0·02). Conclusions The results suggest that, in addition to the major effect of hypoparathyroidism, hypothyroidism may play a role in hypocalcaemia in 22q11·2DS and that there is a high recurrence rate of neonatal hypocalcaemia. Hypomagnesaemia may contribute to hypocalcaemia by further suppressing parathyroid hormone (PTH). Although further studies are needed, the findings support regular lifelong follow-up of calcium, magnesium, PTH and TSH levels in patients with 22q11·2DS. At any age, hypocalcaemia with hypoparathyroidism and/or hypothyroidism may suggest a diagnosis of 22q11·2DS. PMID:24735350

Cheung, Evelyn Ning Man; George, Susan R; Costain, Gary A; Andrade, Danielle M; Chow, Eva W C; Silversides, Candice K; Bassett, Anne S

2014-01-01

153

Hearing loss in a mouse model of 22q11.2 Deletion Syndrome.  

PubMed

22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM. PMID:24244619

Fuchs, Jennifer C; Zinnamon, Fhatarah A; Taylor, Ruth R; Ivins, Sarah; Scambler, Peter J; Forge, Andrew; Tucker, Abigail S; Linden, Jennifer F

2013-01-01

154

Hearing Loss in a Mouse Model of 22q11.2 Deletion Syndrome  

PubMed Central

22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM. PMID:24244619

Fuchs, Jennifer C.; Zinnamon, Fhatarah A.; Taylor, Ruth R.; Ivins, Sarah; Scambler, Peter J.; Forge, Andrew; Tucker, Abigail S.; Linden, Jennifer F.

2013-01-01

155

Detection of cryptic chromosomal abnormalities in unexplained mental retardation: A general strategy using hypervariable subtelomeric DNA polymorphisms  

SciTech Connect

Given the availability of DNA from both parents, unusual segregation of hypervariable DNA polymorphisms (HVPs) in the offspring may be attributable to deletion, unbalanced chromosomal translocation, or uniparental disomy. The telomeric regions of chromosomes are rich in both genes and hypervariable minisatellite sequences and may also be particularly prone to cryptic breakage events. Here the author describes and analyzes a general approach to the detection of subtelomeric abnormalities and uniparental disomy in patients with unexplained mental retardation. With 29 available polymorphic systems, [approximately]50%-70% of these abnormalities could currently be detected. Development of subtelomeric HVPs physically localized with respect to their telomers should provide a valuable resource in routine diagnostics. 73 refs., 4 figs., 4 tabs.

Wilkie, A.O.M.

1993-09-01

156

Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature  

PubMed Central

Rett syndrome is a severe neurodegenerative disorder characterized by acquired microcephaly, communication dysfunction, psychomotor regression, seizures and stereotypical hand movements. Mutations in methyl CpG binding protein 2 (MECP2) are identified in most patients with classic Rett syndrome. Genetic studies in patients with a Rett variant have expanded the spectrum of underlying genetic etiologies. Recently, a deletion encompassing several genes in the long arm of chromosome 14 has been associated with the congenital Rett-syndrome phenotype. Using array-based comparative genomic hybridization, we identified a 3-year-old female with a Rett-like syndrome carrying a de novo single-gene deletion of FOXG1. Her presentation included intellectual disability, epilepsy and a Rett-like phenotype. The variant features included microcephaly at birth and prominent synophrys. Our results confirm that congenital Rett syndrome can be caused by copy-number variation in FOXG1 and expand the clinical phenotypic spectrum of FOXG1 defect in humans. PMID:19623215

Jacob, Francois Dominique; Ramaswamy, Vijay; Andersen, John; Bolduc, Francois V

2009-01-01

157

Intelligence and Visual Motor Integration in 5-Year-Old Children with 22q11-Deletion Syndrome  

ERIC Educational Resources Information Center

The purpose of this study was to explore the relationship between intelligence and visual motor integration skills in 5-year-old children with 22q11-deletion syndrome (22q11DS) (N = 65, 43 females, 22 males; mean age 5.6 years (SD 0.2), range 5.23-5.99 years). Sufficient VMI skills seem a prerequisite for IQ testing. Since problems related to…

Duijff, Sasja; Klaassen, Petra; Beemer, Frits; Swanenburg de Veye, Henriette; Vorstman, Jacob; Sinnema, Gerben

2012-01-01

158

Common deleted genes in the 5q? syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice  

Microsoft Academic Search

The commonly deleted region (CDR) for the 5q? syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)–PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q? samples that showed the most pronounced decrease in expression compared to

S Lehmann; J O'Kelly; S Raynaud; S E Funk; E H Sage; H P Koeffler

2007-01-01

159

Epilepsy phenotype associated with a chromosome 2q24.3 deletion involving SCN1A: Migrating partial seizures of infancy or atypical Dravet syndrome?  

PubMed

The deletion of a sodium channel gene cluster located on chromosome 2q24.3 is associated with variable epilepsy phenotypes, including Dravet syndrome and migrating partial seizures of infancy. Although SCN1A is considered as the major contributor to the epilepsy phenotype, the role of other sodium channel genes that map within this cluster has not been delineated. We presented five new cases with a chromosome 2q24.3 deletion involving SCN1A and investigated their epilepsy phenotype in relation to the extent of the deletion. Three cases with deletion of the whole sodium channel gene cluster (SCN3A, SCN2A, SCN1A, SCN9A, and SCN7A) exhibited a complex epilepsy phenotype that was atypical for Dravet syndrome and suggestive of migrating partial seizures of infancy: early seizure onset (before 2 months of age), severe developmental delay from seizure onset, multifocal interictal spikes, polymorphous focal seizures, and acquired microcephaly. Two cases with partial deletion of SCN1A and SCN9A and whole SCN1A deletion had an epilepsy phenotype of Dravet syndrome. A literature review of cases with chromosome 2q24.3 deletion revealed that, in most Dravet syndrome cases, it does not involve SCN2A and SCN3A, whereas a complex epilepsy phenotype that is shared with migrating partial seizures of infancy was associated with cases of deletion of the whole sodium channel gene cluster. PMID:25524840

Lim, Byung Chan; Hwang, Hee; Kim, Hunmin; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Yum, Mi-Sun; Ko, Tae-Sung

2015-01-01

160

Myelodysplastic syndromes with 5q deletion: pathophysiology and role of lenalidomide.  

PubMed

Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q deletion (del(5q)) as the culprit pathogenetic trigger. Del(5q) affects critical regions 5q31 and 5q33, leading to gene haplodeficiency with subsequent RPS14 haplodeficiency and P53 activation. Subsequent to P53 activation, erythroid cell apoptosis and ineffective erythropoiesis occur. Other pathogenetic elements include protein phosphatase 2a and CDC25C haplodeficiency and decreased miR-145 and miR-146a expression. Lenalidomide is an immunomodulatory agent that selectively suppresses the del(5q) clone. While the mechanism is not fully understood, it is associated with diverse molecular changes including stabilization of MDM2 with subsequent enhanced P53 degradation. Lenalidomide showed success in low- and intermediate-1-risk MDS as reported in the 002, 003, and 004 trials. However, in higher-risk MDS, the results of lenalidomide monotherapy were modest, mandating the use of combination therapy. The role and priority of lenalidomide varies between different guidelines, and accordingly, future efforts are necessary to reach a unified therapeutic algorithm. TP53 mutations are important predictors of AML progression and possible resistance to lenalidomide. It is recommended to identify TP53 mutation early in the disease since it may change the decision regarding choice of therapy. Challenges with lenalidomide therapy remain the long-term effects and timing of its discontinuation. PMID:24627193

Gaballa, Mahmoud R; Besa, Emmanuel C

2014-05-01

161

Prodromal and autistic symptoms in schizotypal personality disorder and 22q11.2 deletion syndrome.  

PubMed

Despite clear diagnostic distinctions, schizophrenia and autism share symptoms on several dimensions. Recent research has suggested the two disorders overlap in etiology, particularly with respect to inherited and noninherited genetic factors. Studying the relationship between psychotic-like and autistic-like symptoms in risk groups such as 22q11 deletion syndrome (22q11DS) and schizotypal personality disorder (SPD) has the potential to shed light on such etiologic factors; thus, the current study examined prodromal symptoms and autistic features in samples of 22q11DS and SPD subjects using standardized diagnostic measures, including the Structured Interview for Prodromal Symptoms (SIPS) and the Autism Diagnostic Inventory-Revised (ADI-R). Results showed that SPD subjects manifested significantly more severe childhood and current social as well as stereotypic autistic features, as well as more severe positive prodromal symptoms. The two groups did not differ on negative, disorganized, or general prodromal symptoms, but were distinguishable based on correlations between prodromal and autistic features; the relationships between childhood autistic features and current prodromal symptoms were stronger for the SPD group. The results suggest that childhood autistic features are less continuous with subsequent prodromal signs in 22q11DS patients relative to those with SPD, and the findings highlight the importance of studying the overlap in diagnostic phenomenology in groups at risk for developing psychosis and/or autism. PMID:22686870

Esterberg, Michelle L; Ousley, Opal Y; Cubells, Joseph F; Walker, Elaine F

2013-02-01

162

Brain and Behavior in Children with 22Q11.2 Deletion Syndrome: A Volumetric and Voxel-Based Morphometry MRI Study  

ERIC Educational Resources Information Center

In people with velo-cardio-facial syndrome [or 22q11.2 deletion syndrome (22qDS)], a single interstitial deletion of chromosome 22q11.2 causes a wide spectrum of cognitive deficits ranging from global learning difficulties to specific cognitive deficits. People with 22qDS are also at high risk of developing attention-deficit hyperactivity disorder…

Campbell, Linda E.; Daly, Eileen; Toal, Fiona; Stevens, Angela; Azuma, Rayna; Catani, Marco; Ng, Virginia; Van Amelsvoort, Therese; Chitnis, Xavier; Cutter, William; Murphy, Declan G. M.; Murphy, Kieran C.

2006-01-01

163

Similar molecular deletions on chromosome 15q11.2 are encountered in both the Prader-Willi and Angelman syndromes  

Microsoft Academic Search

Comparative molecular analysis of chromosome 15, sub-band q11.2 of patients with the Prader-Willi or Angelman syndromes demonstrates that they have a similar deletion. An hypothesis is presented that attempts to explain the tremendous degree of clinical heterogeneity in these diverse deletion-associated syndromes based on abnormal haplotypes present on the cytogenetically normal homolog. This hypothesis also addresses genetic similarities between patients

T. A. Donlon

1988-01-01

164

Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes  

PubMed Central

We present two patients with the full Williams syndrome (WS) phenotype carrying a smaller deletion than typically observed. The deleted region spans from the elastin gene to marker D7S1870. This observation narrows the minimal region of deletion in WS and suggests that the syntaxin 1A and frizzled genes are not responsible for the major features of this developmental disorder and provides important insight into understanding the genotype-phenotype correlation in WS.???Keywords: Williams syndrome; elastin; syntaxin; frizzled PMID:10874638

Botta, A; Novelli, G; Mari, A; Novelli, A; Sabani, M; Korenberg, J; Osborne, L; Digilio, M; Giannotti, A; Dallapiccola, B

1999-01-01

165

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes  

PubMed Central

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin. PMID:23453669

Delio, Maria; Guo, Tingwei; McDonald-McGinn, Donna M.; Zackai, Elaine; Herman, Sean; Kaminetzky, Mark; Higgins, Anne Marie; Coleman, Karlene; Chow, Carolyn; Jarlbrzkowski, Maria; Bearden, Carrie E.; Bailey, Alice; Vangkilde, Anders; Olsen, Line; Olesen, Charlotte; Skovby, Flemming; Werge, Thomas M.; Templin, Ludivine; Busa, Tiffany; Philip, Nicole; Swillen, Ann; Vermeesch, Joris R.; Devriendt, Koen; Schneider, Maude; Dahoun, Sophie; Eliez, Stephan; Schoch, Kelly; Hooper, Stephen R.; Shashi, Vandana; Samanich, Joy; Marion, Robert; van Amelsvoort, Therese; Boot, Erik; Klaassen, Petra; Duijff, Sasja N.; Vorstman, Jacob; Yuen, Tracy; Silversides, Candice; Chow, Eva; Bassett, Anne; Frisch, Amos; Weizman, Abraham; Gothelf, Doron; Niarchou, Maria; van den Bree, Marianne; Owen, Michael J.; Suñer, Damian Heine; Andreo, Jordi Rosell; Armando, Marco; Vicari, Stefano; Digilio, Maria Cristina; Auton, Adam; Kates, Wendy R.; Wang, Tao; Shprintzen, Robert J.; Emanuel, Beverly S.; Morrow, Bernice E.

2013-01-01

166

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.  

PubMed

Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR. PMID:23486540

Higashimoto, Ken; Maeda, Toshiyuki; Okada, Junichiro; Ohtsuka, Yasufumi; Sasaki, Kensaku; Hirose, Akiko; Nomiyama, Makoto; Takayanagi, Toshimitsu; Fukuzawa, Ryuji; Yatsuki, Hitomi; Koide, Kayoko; Nishioka, Kenichi; Joh, Keiichiro; Watanabe, Yoriko; Yoshiura, Koh-ichiro; Soejima, Hidenobu

2013-11-01

167

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome  

PubMed Central

Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR. PMID:23486540

Higashimoto, Ken; Maeda, Toshiyuki; Okada, Junichiro; Ohtsuka, Yasufumi; Sasaki, Kensaku; Hirose, Akiko; Nomiyama, Makoto; Takayanagi, Toshimitsu; Fukuzawa, Ryuji; Yatsuki, Hitomi; Koide, Kayoko; Nishioka, Kenichi; Joh, Keiichiro; Watanabe, Yoriko; Yoshiura, Koh-ichiro; Soejima, Hidenobu

2013-01-01

168

Platybasia in 22q11.2 Deletion Syndrome Is Not Correlated with Speech Resonance  

PubMed Central

Background An abnormally obtuse cranial base angle, also known as platybasia, is a common finding in patients with 22q11.2 deletion syndrome (22q11DS). Platybasia increases the depth of the velopharynx and is therefore postulated to contribute to velopharyngeal dysfunction. Our objective was to determine the clinical significance of platybasia in 22q11DS by exploring the relationship between cranial base angles and speech resonance. Methods In this retrospective chart review at a tertiary hospital, 24 children (age, 4.0-13.1 years) with 22q11.2DS underwent speech assessments and lateral cephalograms, which allowed for the measurement of the cranial base angles. Results One patient (4%) had hyponasal resonance, 8 (33%) had normal resonance, 10 (42%) had hypernasal resonance on vowels only, and 5 (21%) had hypernasal resonance on both vowels and consonants. The mean cranial base angle was 136.5° (standard deviation, 5.3°; range, 122.3-144.8°). The Kruskal-Wallis test showed no significant relationship between the resonance ratings and cranial base angles (P=0.242). Cranial base angles and speech ratings were not correlated (Spearman correlation=0.321, P=0.126). The group with hypernasal resonance had a significantly more obtuse mean cranial base angle (138° vs. 134°, P=0.049) but did not have a greater prevalence of platybasia (73% vs. 56%, P=0.412). Conclusions In this retrospective chart review of patients with 22q11DS, cranial base angles were not correlated with speech resonance. The clinical significance of platybasia remains unknown. PMID:25075355

Kon, Moshe; Mink van der Molen, Aebele B

2014-01-01

169

Deletion 17p11.2 (Smith-Magenis syndrome) is relatively common among patients having mental retardation and myopia  

SciTech Connect

We recently reported the finding of moderate to severe myopia in 6 of 10 patients with Smith-Magenis syndrome (SMS). To investigate the prevalence of SMS among mentally retarded people having myopia, we surveyed a cohort of patients residing at a facility for individuals with mental retardation (MR). Of 547 institutionalized individuals with MR, 72 (13.2%) had moderate to high myopia defined as a visual acuity of minus 3 diopters or more. It should be noted that our institution does not specifically select for people with visual impairment; rather, the facility serves people with a primary diagnosis of MR. Sixty-five of 72 (90.3%) myopic individuals identified were available for cytogenetic analysis. Seventeen (26.2%) of these patients had trisomy 21. Down syndrome (DS) is well known to be associated with eye abnormalities, including myopia. Of 48 individuals with moderate to high myopia not having DS, 5 (10.4%) were shown to have deletions of 17p11.2. This is a high prevalence considering the relative rarity of SMS. By contrast, in a randomized sample of 48 patients without significant myopia at the same facility, we found no individuals with deletion 17p11.2. We conclude that the diagnosis of SMS should be considered in any non-Down syndrome individual having MR and myopia, and that ophthalmologists serving people with MR should be made aware of this deletion syndrome. Furthermore, our results suggest that significant numbers of people having SMS could be identified through selective institutional screening of patients having a combination of MR and moderate to severe myopia.

Finucane, B.; Jaeger, E.R. [Elwyn, Inc. PA (United States); Freitag, S.K. [Jefferson Medical College, Philadelphia, PA (United States)

1994-09-01

170

Otitis Media in a New Mouse Model for CHARGE Syndrome with a Deletion in the Chd7 Gene  

PubMed Central

Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-?1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome. PMID:22539951

Tian, Cong; Yu, Heping; Yang, Bin; Han, Fengchan; Zheng, Ye; Bartels, Cynthia F.; Schelling, Deborah; Arnold, James E.; Scacheri, Peter C.; Zheng, Qing Yin

2012-01-01

171

Individuals with 22q11.2 Deletion Syndrome Are Impaired at Explicit, but Not Implicit, Discrimination of Local Forms Embedded in Global Structures  

ERIC Educational Resources Information Center

Individuals with 22q11.2 deletion syndrome (22q11.2DS) are impaired at exploring visual information in space; however, not much is known about visual form discrimination in the syndrome. Thirty-five individuals with 22q11.2DS and 41 controls completed a form discrimination task with global forms made up of local elements. Affected individuals…

Giersch, Anne; Glaser, Bronwyn; Pasca, Catherine; Chabloz, Mélanie; Debbané, Martin; Eliez, Stephan

2014-01-01

172

Chromosome 2q37 deletion: clinical and molecular aspects.  

PubMed

Terminal deletions of chromosome 2 with breakpoints at or within band 2q37, ranging from visible abnormalities to cryptic, subtelomeric deletions, have been recognized with increasing frequency among children with mild-moderate mental retardation, characteristic facial appearance, and behavioral manifestations which often place them on the autism spectrum. The stereotypic facial characteristics include prominent forehead, thin, highly arched eyebrows, depressed nasal bridge, full cheeks, deficient nasal alae and prominent columella, thin upper lip, and various minor anomalies of the pinnae. Abnormal nipples, including inverted nipples, have been reported in a number of cases. CNS, ocular, cardiac, gastrointestinal, renal, and other GU anomalies have been noted in nearly one-third of patients. Of note, coarctation or hypoplasia of the aorta has been described in several affected children. Wilms tumor, renal dysplasia, and tracheomalacia have been reported only with the most proximal breakpoint at band 2q37.1 while a range of GI anomalies, pyloric stenosis, and diaphragmatic defects have been reported with breakpoints throughout the region. A subset of patients with the most distal deletion present phenotypic features which mimic Albright hereditary osteodystrophy (AHO). In addition to the AHO-like phenotype, later onset findings include seizures and cystic kidneys. Timely diagnosis of this recognizable syndrome provides a basis for genetic counseling, appropriate surveillance, and intervention, and avoids unnecessary and expensive diagnostic testing. PMID:17910077

Falk, Rena E; Casas, Kari A

2007-11-15

173

De novo deletion of chromosome 11q12.3 in monozygotic twins affected by Poland Syndrome  

PubMed Central

Background Poland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown. Case presentation Here we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways. Conclusions Phenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development. PMID:24885342

2014-01-01

174

Occupational hydrocarbon exposure among fathers of Prader-Willi syndrome patients with and without deletions of 15q  

SciTech Connect

Prader-Willi syndrome (PWS) is a multiple-anomaly disorder in which 50%-70% of cases are associated with a de novo interstitial deletion (del 15(q11-13)) on prometaphase cytogenetic analysis, the remainder having apparently normal chromosomes. In most instances, the paternally derived chromosome has become deleted in the affected child, suggesting the possibility of a predisposing environmental factor. Strakowski and Butler found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations in this population. This observation may suggest a causal relationship to PWS. To determine whether this association may distinguish the cytogenetically different groups, we identified 81 patients with the disorder who were physically and cytogenetically examined in three centers, and we compared the frequency of possible periconceptional occupational hydrocarbon exposure between fathers of patients who demonstrate a 15q deletion and those who do not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half of the fathers had been employed in hydrocarbon-exposing jobs. These findings suggest lack of etiologic heterogeneity between the cytogenetically different groups for PWS and affirm the need to seek submicroscopic deletions through molecular genetic studies. These data also provide additional evidence that hydrocarbon exposure among fathers of children with PWS may be causally related to the disorder, and they also suggest the need for more accurate assessment of exposure via a large, controlled study.

Cassidy, S.B.; Gainey, A.J.; Butler, M.G.

1989-06-01

175

Smith-Magenis syndrome deletion: A case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization  

SciTech Connect

The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith-Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400-550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism. 23 refs., 3 figs., 1 tab.

Juyal, R.C.; Patel, P.I.; Greenberg, F. [Baylor College of Medicine, Houston, TX (United States)] [and others

1995-09-11

176

Occupational hydrocarbon exposure among fathers of Prader-Willi syndrome patients with and without deletions of 15q.  

PubMed

Prader-Willi syndrome (PWS) is a multiple-anomaly disorder in which 50%-70% of cases are associated with a de novo interstitial deletion [del 15(q11-13)] on prometaphase cytogenetic analysis, the remainder having apparently normal chromosomes. In most instances, the paternally derived chromosome has become deleted in the affected child, suggesting the possibility of a predisposing environmental factor. Strakowski and Butler found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations in this population. This observation may suggest a causal relationship to PWS. To determine whether this association may distinguish the cytogenetically different groups, we identified 81 patients with the disorder who were physically and cytogenetically examined in three centers, and we compared the frequency of possible periconceptional occupational hydrocarbon exposure between fathers of patients who demonstrate a 15q deletion and those who do not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half of the fathers had been employed in hydrocarbon-exposing jobs. These findings suggest lack of etiologic heterogeneity between the cytogenetically different groups for PWS and affirm the need to seek submicroscopic deletions through molecular genetic studies. These data also provide additional evidence that hydrocarbon exposure among fathers of children with PWS may be causally related to the disorder, and they also suggest the need for more accurate assessment of exposure via a large, controlled study. PMID:2729276

Cassidy, S B; Gainey, A J; Butler, M G

1989-06-01

177

Delineation of 2q32q35 Deletion Phenotypes: Two Apparent “Proximal” and “Distal” Syndromes  

PubMed Central

We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1–q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6?Mb deletion in patients 1 and 2 and a 24.7?Mb deletion in patient 3. We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2, and CPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene. PMID:23840981

Taylor, Juliet; Gregersen, Nerine; George, Alice M.; Love, Donald R.

2013-01-01

178

Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in Non-Hodgkin¿s Lymphoma.  

PubMed

Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin¿s Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated. PMID:25376092

Guenat, David; Quentin, Samuel; Rizzari, Carmelo; Lundin, Catarina; Coliva, Tiziana; Edery, Patrick; Fryssira, Helen; Bermont, Laurent; Ferrand, Christophe; Soulier, Jean; Christophe, Borg; Rohrlich, Pierre-Simon

2014-11-01

179

Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in non-Hodgkin lymphoma.  

PubMed

Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated. PMID:25388916

Guenat, David; Quentin, Samuel; Rizzari, Carmelo; Lundin, Catarina; Coliva, Tiziana; Edery, Patrick; Fryssira, Helen; Bermont, Laurent; Ferrand, Christophe; Soulier, Jean; Borg, Christophe; Rohrlich, Pierre-Simon

2014-01-01

180

A review of neurocognitive and behavioral profiles associated with 22q11 deletion syndrome: implications for clinical evaluation and treatment.  

PubMed

22q11 deletion syndrome (22q11DS) is a chromosomal disorder that results in variable multisystem abnormalities, including conotruncal cardiac malformations, aplasia or hypoplasia of the thymus and/or parathyroid glands, immunodeficiency, dysmorphic facial features, and cleft palate and other nasopharyngeal and dental anomalies. Individuals with 22q11DS also exhibit cognitive and behavioral difficulties, including delayed motor and speech-language development, mental retardation, low academic achievement, impaired spatial reasoning, poor attentional and executive functioning, attention-deficit hyperactivity disorder, autism spectrum disorders, mood disorders, and/or schizophrenia spectrum disorders. Interventions should be designed based on the results of periodic developmental and neuropsychological assessments and psychiatric screening. Future research should focus on understanding deletion-related gene-environment interactions and their effects on developmental and behavioral outcomes, identifying neurodegenerative processes in 22q11DS, and developing preventive models of behavioral and psychopharmacologic treatment. PMID:17389127

Ousley, Opal; Rockers, Kimberly; Dell, Mary Lynn; Coleman, Karlene; Cubells, Joseph F

2007-04-01

181

Genetic Dosage Compensation in a Family with Velo-cardio-facial/DiGeorge/22q11.2 Deletion Syndrome  

PubMed Central

Cytogenetic studies of a male child carrying the 22q11.2 deletion common in patients with velo-cardio-facial/DiGeorge syndrome revealed an unexpected rearrangement of the 22q11.2 region in his normal appearing mother. The mother carries a 3 Mb deletion on one copy and a reciprocal, similar sized duplication on the other copy of chromosome 22q11.2 as revealed by fluorescence in situ hybridization and array comparative genome hybridization analysis. The most parsimonious mechanism for the rearrangement is a mitotic non-allelic homologous recombination event in a cell in the early embryo soon after fertilization. The normal phenotype of the mother can be explained by the theory of genetic dosage compensation. This is the second documented case of such an event for this or any genomic disorder. This finding helps to reinforce this phenomenon in a human model, and has significant implications for genetic counseling of future children. PMID:21337693

Alkalay, Avishai A.; Guo, Tingwei; Montagna, Cristina; Digilio, M. Cristina; Marino, Bruno; Dallapiccola, Bruno; Morrow, Bernice

2014-01-01

182

Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions  

PubMed Central

Background The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM. Methods and results Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q. Conclusions Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS. PMID:23679990

2013-01-01

183

Segregation of a novel homozygous 6 nucleotide deletion in GLUT2 gene in a Fanconi-Bickel syndrome family.  

PubMed

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, impaired utilization of glucose and galactose, rickets, and severe short stature. It has been shown to be caused by mutations in GLUT2 gene, a member of the facilitative glucose transporter family. Here, we report an Iranian family with 2 affected siblings. The clinical findings in the patients include developmental delay, failure to thrive, hepatomegaly, enlarged kidneys and rickets. A novel 6 nucleotide deletion (c.1061_1066del6, p.V355_S356del2) is shown to be segregated with the disease in this family. PMID:25523092

Abbasi, Farzaneh; Azizi, Faezeh; Javaheri, Mona; Mosallanejad, Asieh; Ebrahim-Habibi, Azadeh; Ghafouri-Fard, Soudeh

2015-02-15

184

A review of neurocognitive and behavioral profiles associated with 22q11 deletion syndrome: Implications for clinical evaluation and treatment  

Microsoft Academic Search

22q11 deletion syndrome (22q11DS) is a chromosomal disorder that results in variable multisystem abnormalities, including\\u000a conotruncal cardiac malformations, aplasia or hypoplasia of the thymus and\\/or parathyroid glands, immunodeficiency, dysmorphic\\u000a facial features, and cleft palate and other nasopharyngeal and dental anomalies. Individuals with 22q11DS also exhibit cognitive\\u000a and behavioral difficulties, including delayed motor and speech-language development, mental retardation, low academic achievement,

Opal Ousley; Kimberly Rockers; Mary Lynn Dell; Karlene Coleman; Joseph F. Cubells

2007-01-01

185

Atypical Association of Angelman Syndrome and Klinefelter Syndrome in a Boy with 47,XXY Karyotype and Deletion 15q11.2-q13.  

PubMed

Angelman syndrome (AS, OMIM 105830) is a neurogenetic disorder with firm clinical diagnostic guidelines, characterized by severe developmental delay and speech impairment, balanced and behavioral disturbance as well as microcephaly, seizures, and a characteristic electroencephalogram (EEG). The majority of AS cases (70%) are caused by a 15q11.2-q13 deletion on the maternally derived chromosome. The frequency of AS has been estimated to be between 1/10000 and 1/20000. Klinefelter syndrome (KS) occurs due to the presence of an extra X chromosome (karyotype 47,XXY). The main features in KS are small testes, hypergonadotropic hypogonadism, gynecomastia, learning difficulties, and infertility. We present what is, to our knowledge, the first case of a patient with both KS and AS due to a 15q11.2-q13 deletion on the maternally derived chromosome and an extra X chromosome of paternal origin. He showed dysmorphic features, axial hypotonia, and delayed acquisition of motor skills. Early diagnosis is essential for optimal treatment of AS children; this is one of the earliest diagnosed cases of AS probably due to the presence of two syndromes. Clinical findings in this patient here described may be helpful to identify any other cases and to evaluate recurrence risks in these families. PMID:25379297

Sánchez, Javier; Peciña, Ana; Alonso-Luengo, Olga; González-Meneses, Antonio; Vázquez, Rocío; Antiñolo, Guillermo; Borrego, Salud

2014-01-01

186

Problem Behaviors Associated with Deletion Prader-Willi, Smith-Magenis, and Cri Du Chat Syndromes.  

ERIC Educational Resources Information Center

Problem behaviors of 38 individuals with Cri-du-Chat syndrome, 55 individuals with Prader Willi syndrome, and 21 individuals with Smith-Magenis syndrome were investigated. All three disorders were Associated with greater ratings of problem behaviors (besides eating abnormalities and sleep abnormalities) than comparison groups. (Author/CR)

Clarke, David J.; Boer, Harm

1998-01-01

187

Deletion 2q37: an identifiable clinical syndrome with mental retardation and autism.  

PubMed

Terminal deletion of the long arm of chromosome 2 is a rare chromosomal disorder characterized by low birth weight, delayed somatic and mental development, craniofacial defects, short neck, heart and lung congenital defects, and autistic features. We report on a girl with 46,XX.ish del(2)(q37.1) de novo karyotype, mental retardation, dysmorphic features, gastrointestinal anomalies, and autistic traits and compare her clinical manifestations with patients with the same deletion previously described in literature. PMID:18658079

Galasso, Cinzia; Lo-Castro, Adriana; Lalli, Cristina; Nardone, Anna Maria; Gullotta, Francesca; Curatolo, Paolo

2008-07-01

188

A Saudi Patient with an Interstitial Deletion of Short Arm of Chromosome 3 (p13 to p21) and its Association with Joubert's Syndrome Features  

PubMed Central

We report a case of 4 weeks old girl with a de novo interstitial deletion of the short arm of chromosome 3 (p13-p21) and clinical findings typical of proximal 3p deletion together with heart defects, choanal atresia, ear anomalies, central nervous system anomalies, renal anomalies and associated Joubert's syndrome (JS). Family history is unremarkable and parenteral chromosomes were normal. The clinical manifestations of the patient are compared with those of 11 patients previously described with a proximal 3p deletion. The additional JS features associated with this syndrome were described. This is the first case report in English literature describing 3p deletion associated with additional JS features. PMID:24027747

Mersal, Ali Y.; Basha, Mahaboob K.; Brinji, Zaina S.; Avand, Ghazal

2013-01-01

189

Implications for genotype-phenotype predictions in Townes-Brocks syndrome: case report of a novel SALL1 deletion and review of the literature.  

PubMed

Townes-Brocks syndrome (TBS) is a well-described genetic syndrome characterized by anal, ear, and thumb anomalies and variable expressivity. Over 60 nonsense and frameshift mutations have been identified in SALL1, the zinc finger transcription factor causing TBS, and are proposed to cause disease via a dominant negative mechanism. In contrast, only four deletions have been described, with mild phenotypes reported as a result of haploinsufficiency. We report on a family with features of TBS in whom a novel 149?kb deletion spanning the SALL1 gene was identified by high resolution cytogenetics SNP microarray. We review the available genotype-phenotype information for all known truncating mutations and deletions. Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism. PMID:22308078

Miller, Erin M; Hopkin, Robert; Bao, Liming; Ware, Stephanie M

2012-03-01

190

Chromosome Deletion of 14q32.33 Detected by Array Comparative Genomic Hybridization in a Patient with Features of Dubowitz Syndrome  

PubMed Central

We report a 4-year-old girl of Mexican origins with a clinical diagnosis of Dubowitz syndrome who carries a de novo terminal deletion at the 14q32.33 locus identified by array comparative genomic hybridization (aCGH). Dubowitz syndrome is a rare condition characterized by a constellation of features including growth retardation, short stature, microcephaly, micrognathia, eczema, telecanthus, blepharophimosis, ptosis, epicanthal folds, broad nasal bridge, round-tipped nose, mild to moderate developmental delay, and high-pitched hoarse voice. This syndrome is thought to be autosomal recessive; however, the etiology has not been determined. This is the first report of this deletion in association with this phenotype; it is possible that this deletion may be causal for a Dubowitz phenocopy. PMID:23074674

Darcy, Diana C.; Rosenthal, Scott; Wallerstein, Robert J.

2011-01-01

191

Chromosome deletion of 14q32.33 detected by array comparative genomic hybridization in a patient with features of dubowitz syndrome.  

PubMed

We report a 4-year-old girl of Mexican origins with a clinical diagnosis of Dubowitz syndrome who carries a de novo terminal deletion at the 14q32.33 locus identified by array comparative genomic hybridization (aCGH). Dubowitz syndrome is a rare condition characterized by a constellation of features including growth retardation, short stature, microcephaly, micrognathia, eczema, telecanthus, blepharophimosis, ptosis, epicanthal folds, broad nasal bridge, round-tipped nose, mild to moderate developmental delay, and high-pitched hoarse voice. This syndrome is thought to be autosomal recessive; however, the etiology has not been determined. This is the first report of this deletion in association with this phenotype; it is possible that this deletion may be causal for a Dubowitz phenocopy. PMID:23074674

Darcy, Diana C; Rosenthal, Scott; Wallerstein, Robert J

2011-01-01

192

Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles.  

PubMed

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions. PMID:21647151

Loudin, M G; Wang, J; Leung, H-C Eastwood; Gurusiddappa, S; Meyer, J; Condos, G; Morrison, D; Tsimelzon, A; Devidas, M; Heerema, N A; Carroll, A J; Plon, S E; Hunger, S P; Basso, G; Pession, A; Bhojwani, D; Carroll, W L; Rabin, K R

2011-10-01

193

Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL).  

PubMed

Recognition of the gene implicated in a Mendelian disorder subsequently leads to an expansion of potential phenotypes associated with mutations in that gene as patients with features beyond the core phenotype are identified by sequencing. Here, we present a young girl with developmental delay, short stature despite a markedly advanced bone age, hypertrichosis without elbow hair, renal anomalies, and dysmorphic facial features, found to have a heterozygous, de novo, intragenic deletion encompassing exons 2-10 of the KMT2A (MLL) gene detected by whole exome sequencing. Heterozygous mutations in this gene were recently demonstrated to cause Wiedemann-Steiner syndrome (OMIM 605130). Importantly, retrospective analysis of this patient's chromosomal microarray revealed decreased copy number of two probes corresponding to exons 2 and 9 of the KMT2A gene, though this result was not reported by the testing laboratory in keeping with standard protocols for reportable size cutoffs for array comparative genomic hybridization. This patient expands the clinical phenotype associated with mutations in KMT2A to include variable patterns of hypertrichosis and a significantly advanced bone age with premature eruption of the secondary dentition despite her growth retardation. This patient also represents the first report of Wiedemann-Steiner syndrome due to an exonic deletion, supporting haploinsufficiency as a causative mechanism. Our patient also illustrates the need for sensitive guidelines for the reporting of chromosomal microarray findings that are below traditional reporting size cutoffs, but that impact exons or other genomic regions of known function. PMID:24818805

Mendelsohn, Bryce A; Pronold, Melissa; Long, Roger; Smaoui, Nizar; Slavotinek, Anne M

2014-08-01

194

Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans  

PubMed Central

Objective: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. Methods: We identified 2 families with cerebellar ataxia, eye movement abnormalities, and global developmental delay. We performed genetic analyses including single nucleotide polymorphism genotyping, linkage analysis, array comparative genomic hybridization, quantitative PCR, and Sanger sequencing. We obtained eye movement recordings of mutant mice deficient for the ortholog of the identified candidate gene, and performed immunohistochemistry using human and mouse brain specimens. Results: All affected individuals had ataxia, eye movement abnormalities, most notably tonic upgaze, and delayed speech and cognitive development. Homozygosity mapping identified the disease locus on chromosome 4q. Within this region, a homozygous deletion of GRID2 exon 4 in the index family and compound heterozygous deletions involving GRID2 exon 2 in the second family were identified. Grid2-deficient mice showed larger spontaneous and random eye movements compared to wild-type mice. In developing mouse and human cerebella, GRID2 localized to the Purkinje cell dendritic spines. Brain MRI in 2 affected children showed progressive cerebellar atrophy, which was more severe than that of Grid2-deficient mice. Conclusions: Biallelic deletions of GRID2 lead to a syndrome of cerebellar ataxia and tonic upgaze in humans. The phenotypic resemblance and similarity in protein expression pattern between humans and mice suggest a conserved role for GRID2 in the synapse organization between parallel fibers and Purkinje cells. However, the progressive and severe cerebellar atrophy seen in the affected individuals could indicate an evolutionarily unique role for GRID2 in the human cerebellum. PMID:24078737

Hills, L. Benjamin; Masri, Amira; Konno, Kotaro; Kakegawa, Wataru; Lam, Anh-Thu N.; Lim-Melia, Elizabeth; Chandy, Nandini; Hill, R. Sean; Partlow, Jennifer N.; Al-Saffar, Muna; Nasir, Ramzi; Stoler, Joan M.; Barkovich, A. James; Watanabe, Masahiko; Yuzaki, Michisuke

2013-01-01

195

Non-Homologous End Joining Repair Mechanism-Mediated Deletion of CHD7 Gene in a Patient with Typical CHARGE Syndrome.  

PubMed

CHARGE syndrome MIM #214800 is an autosomal dominant syndrome involving multiple congenital malformations. Clinical symptoms include coloboma, heart defects, choanal atresia, retardation of growth or development, genital hypoplasia, and ear anomalies or deafness. Mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene have been found in 65-70% of CHARGE syndrome patients. Here, we describe a 16-month-old boy with typical CHARGE syndrome, who was referred for CHD7 gene analysis. Sequence analysis and multiplex ligation-dependent probe amplification were performed. A heterozygous 38,304-bp deletion encompassing exon 3 with a 4-bp insertion was identified. There were no Alu sequences adjacent to the breakpoints, and no sequence microhomology was observed at the junction. Therefore, this large deletion may have been mediated by non-homologous end joining. The mechanism of the deletion in the current case differs from the previously suggested mechanisms underlying large deletions or complex genomic rearrangements in the CHD7 gene, and this is the first report of CHD7 deletion by this mechanism worldwide. PMID:25553296

Lee, Seung Jun; Chae, Jong Hee; Lee, Jung Ae; Cho, Sung Im; Seo, Soo Hyun; Park, Hyunwoong; Seong, Moon-Woo; Park, Sung Sup

2015-01-01

196

Non-Homologous End Joining Repair Mechanism-Mediated Deletion of CHD7 Gene in a Patient with Typical CHARGE Syndrome  

PubMed Central

CHARGE syndrome MIM #214800 is an autosomal dominant syndrome involving multiple congenital malformations. Clinical symptoms include coloboma, heart defects, choanal atresia, retardation of growth or development, genital hypoplasia, and ear anomalies or deafness. Mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene have been found in 65-70% of CHARGE syndrome patients. Here, we describe a 16-month-old boy with typical CHARGE syndrome, who was referred for CHD7 gene analysis. Sequence analysis and multiplex ligation-dependent probe amplification were performed. A heterozygous 38,304-bp deletion encompassing exon 3 with a 4-bp insertion was identified. There were no Alu sequences adjacent to the breakpoints, and no sequence microhomology was observed at the junction. Therefore, this large deletion may have been mediated by non-homologous end joining. The mechanism of the deletion in the current case differs from the previously suggested mechanisms underlying large deletions or complex genomic rearrangements in the CHD7 gene, and this is the first report of CHD7 deletion by this mechanism worldwide. PMID:25553296

Lee, Seung Jun; Chae, Jong Hee; Lee, Jung Ae; Cho, Sung Im; Seo, Soo Hyun; Park, Hyunwoong; Seong, Moon-Woo

2015-01-01

197

Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype.  

PubMed

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype. PMID:15521982

Shrimpton, A E; Braddock, B R; Thomson, L L; Stein, C K; Hoo, J J

2004-12-01

198

A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk  

PubMed Central

Background Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. In this paper we investigate de novo deletions defined as DNA segments missing in an oral cleft proband but present in both unaffected parents. We compare de novo deletion frequencies in children of European ancestry with an isolated, non-syndromic oral cleft to frequencies in children of European ancestry from randomly sampled trios. Results We identified a genome-wide significant 62 kilo base (kb) non-coding region on chromosome 7p14.1 where de novo deletions occur more frequently among oral cleft cases than controls. We also observed wider de novo deletions among cleft lip and palate (CLP) cases than seen among cleft palate (CP) and cleft lip (CL) cases. Conclusions This study presents a region where de novo deletions appear to be involved in the etiology of oral clefts, although the underlying biological mechanisms are still unknown. Larger de novo deletions are more likely to interfere with normal craniofacial development and may result in more severe clefts. Study protocol and sample DNA source can severely affect estimates of de novo deletion frequencies. Follow-up studies are needed to further validate these findings and to potentially identify additional structural variants underlying oral clefts. PMID:24528994

2014-01-01

199

Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome  

PubMed Central

The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis. PMID:23095891

Hofmann, Jennifer J.; Briot, Anais; Enciso, Josephine; Zovein, Ann C.; Ren, Shuxun; Zhang, Zhen W.; Radtke, Freddy; Simons, Michael; Wang, Yibin; Iruela-Arispe, M. Luisa

2012-01-01

200

Pleiotropy in microdeletion syndromes: Neurologic and spermatogenic abnormalities in mice homozygous for the p{sup 6H} deletion are likely due to dysfunction of a single gene  

SciTech Connect

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p{sup 6H} deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p{sup 6H} deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p{sup 6H} deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p{sup 6H} deletion homozygotes. Because etNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p{sup 6H} deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans. 29 refs., 3 figs., 1 tab.

Rinchik, E.M.; Carpenter, D.A. [Oak Ridge National Lab., TN (United States); Handel, M.A. [Univ. of Tennessee, Knoxville, TN (United States)

1995-07-03

201

Expanded Prader-Willi syndrome due to chromosome 15q11.2-14 deletion: report and a review of literature.  

PubMed

We report on a male infant with de novo unbalanced t(5;15) translocation resulting in a 17.23?Mb deletion within 15q11.2-q14 and a 25.12?kb deletion in 5pter. The 15q11.2-q14 deletion encompassed the 15q11.2-q13 Prader-Willi syndrome (PWS) critical region and the recently described 15q13.3 microdeletion syndrome region while the 5pter deletion contained no RefSeq genes. From our literature review, patients with similar deletions in chromosome 15q exhibit expanded phenotype of severe developmental delay, protracted feeding problem, absent speech, central visual impairment, congenital malformations and epilepsy in addition to those typical of PWS. The patient reported herein had previously unreported anomalies of mega cisterna magna, horseshoe kidney and the rare neonatal interstitial lung disease known as pulmonary interstitial glycogenosis. Precise breakpoint delineation by microarray is useful in patients with atypical PWS deletions to guide investigation and prognostication. PMID:23633107

Liu, Anthony P Y; Tang, Wing Fai; Lau, Elizabeth T; Chan, Kelvin Y K; Kan, Anita S Y; Wong, Kar Yin; Tso, Winnie W Y; Jalal, Khair; Lee, So Lun; Chau, Christy S K; Chung, Brian H Y

2013-06-01

202

Relationship between Reaction Time, Fine Motor Control, and Visual-Spatial Perception on Vigilance and Visual-Motor Tasks in 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and…

Howley, Sarah A.; Prasad, Sarah E.; Pender, Niall P.; Murphy, Kieran C.

2012-01-01

203

Discrepancies in Parent and Teacher Ratings of Social-Behavioral Functioning of Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Assessment  

ERIC Educational Resources Information Center

Children with 22q11.2 deletion syndrome exhibit high rates of social-behavioral problems, particularly in the internalizing domain, indicating an area in need of intervention. The current investigation was designed to obtain information regarding parent and teacher ratings of the social-emotional behavior of children with 22q11DS. Using the Child…

Shashi, Vandana; Wray, Emily; Schoch, Kelly; Curtiss, Kathleen; Hooper, Stephen R.

2013-01-01

204

Performance on the Modified Card Sorting Test and Its Relation to Psychopathology in Adolescents and Young Adults with 22Q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

Background: Approximately one-third of individuals with 22q11.2 deletion syndrome (22q11DS), a common genetic disorder highly associated with intellectual disabilities, may develop schizophrenia, likely preceded by a mild to moderate cognitive decline. Methods: We examined adolescents and young adults with 22q11DS for the presence of executive…

Rockers, K.; Ousley, O.; Sutton, T.; Schoenberg, E.; Coleman, K.; Walker, E.; Cubells, J. F.

2009-01-01

205

Association of the Family Environment with Behavioural and Cognitive Outcomes in Children with Chromosome 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

Background: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. Method: Guardians of children with 22q11DS…

Allen, T. M.; Hersh, J.; Schoch, K.; Curtiss, K.; Hooper, S. R.; Shashi, V.

2014-01-01

206

Large-Scale Deletions and SMADIP1 Truncating Mutations in Syndromic Hirschsprung Disease with Involvement of Midline Structures  

PubMed Central

Hirschsprung disease (HSCR) is a common malformation of neural-crest–derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest–derived cells and of CNS but also in the development of midline structures in humans. PMID:11595972

Amiel, Jeanne; Espinosa-Parrilla, Yolanda; Steffann, Julie; Gosset, Philippe; Pelet, Anna; Prieur, Marguerite; Boute, Odile; Choiset, Agnès; Lacombe, Didier; Philip, Nicole; Le Merrer, Martine; Tanaka, Hajime; Till, Marianne; Touraine, Renaud; Toutain, Annick; Vekemans, Michel; Munnich, Arnold; Lyonnet, Stanislas

2001-01-01

207

Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome.  

PubMed

Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis. PMID:24782337

Sana, Maria Elena; Spitaleri, Andrea; Spiliotopoulos, Dimitrios; Pezzoli, Laura; Preda, Laura; Musco, Giovanna; Ferrazzi, Paolo; Iascone, Maria

2014-08-01

208

Molecular approach to analyzing the human 5p deletion syndrome, cri du chat  

Microsoft Academic Search

DNA unique or low-copy fragments were isolated from a genomic DNA library specific for the short (p) arm of human chromosome 5. These chromosome 5p-specific DNA fragments were used to analyze, by Southern blot experiments, somatic cell hybrids that retained either a normal chromosome 5 homolog or a homolog with a partial deletion of 5p, which was derived from either

Leon R. Carlock; John J. Wasmuth

1985-01-01

209

Homozygous deletion in TUSC3 causing syndromic intellectual disability: a new patient.  

PubMed

Defects in the TUSC3 gene have been identified in individuals with nonsyndromic autosomal recessive intellectual disability (ARID), due to either point mutations or intragenic deletions. We report on a boy with a homozygous microdeletion 8p22, sizing 203?kb, encompassing the first exon of the TUSC3 gene, detected by SNP-array analysis (Human Gene Chip 6.0; Affymetrix). Both nonconsanguineous parents come from a small Sicilian village and were heterozygous carriers of the microdeletion. The propositus had a few dysmorphic features and a moderate cognitive impairment. Verbal communication was impaired, with an inappropriate phonetic inventory, important phono-articolatory distortions, and bucco-phonatory dyspraxia. Comprehension was possible for simple sentences. Behavior was characterized by motor instability, high tendency to irritability and distraibility, anxiety traits, and an oppositional-defiant disorder. His parents were of normal intelligence. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltranferase complex that catalyzes a pivotal step in the protein N-glycosylation process. TUSC3 has been recently reported as a member of the plasma membrane Mg(2+) transport system, with a possible involvement in learning abilities, working memory and short- and long-term memory. This is the third family in which a deletion has been described. Although the pathogenic mechanism has not been clarified yet, our report argues for a more prominent role of TUSC3 in the etiology of intellectual disability and that deletions encompassing this gene could be more common than expected. PMID:23825019

Loddo, Sara; Parisi, Valentina; Doccini, Viola; Filippi, Tiziana; Bernardini, Laura; Brovedani, Paola; Ricci, Federica; Novelli, Antonio; Battaglia, Agatino

2013-08-01

210

Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation.  

PubMed

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11. PMID:17036343

Robin, Nathaniel H; Taylor, Clare J; McDonald-McGinn, Donna M; Zackai, Elaine H; Bingham, Peter; Collins, Kevin J; Earl, Dawn; Gill, Deepak; Granata, Tiziana; Guerrini, Renzo; Katz, Naomi; Kimonis, Virginia; Lin, Jean-Pierre; Lynch, David R; Mohammed, Shehla N; Massey, Roger F; McDonald, Marie; Rogers, R Curtis; Splitt, Miranda; Stevens, Cathy A; Tischkowitz, Marc D; Stoodley, Neil; Leventer, Richard J; Pilz, Daniela T; Dobyns, William B

2006-11-15

211

A Physical Map, Including a BAC/PAC Clone Contig, of the Williams-Beuren Syndrome–Deletion Region at 7q11.23  

PubMed Central

Summary Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although ?16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of ?320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region. PMID:10631136

Peoples, Risa; Franke, Yvonne; Wang, Yu-Ker; Pérez-Jurado, Luis; Paperna, Tamar; Cisco, Michael; Francke, Uta

2000-01-01

212

Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan.  

PubMed

In Western countries, gene alterations involving the CRLF2-JAK signaling pathway are identified in approximately 50-60% of patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS-ALL is controversial. IKZF1 deletions, found in 20-30% of DS-ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (?2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients. We confirmed a high incidence of P2RY8-CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8-CRLF2 was slightly lower than that in Western countries (?50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8-CRLF2-positive patients than in P2RY8-CRLF2-negative patients (44% vs. 4%, P=0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8-CRLF2-negative patients (48 and 39%, respectively) but not in P2RY8-CRLF2-positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS-ALL patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients. PMID:25044358

Hanada, Isamu; Terui, Kiminori; Ikeda, Fumika; Toki, Tsutomu; Kanezaki, Rika; Sato, Tomohiko; Kamio, Takuya; Kudo, Ko; Sasaki, Shinya; Takahashi, Yoshihiro; Hayashi, Yasuhide; Inukai, Takeshi; Kojima, Seiji; Koike, Kenichi; Kosaka, Yoshiyuki; Kobayashi, Masao; Imaizumi, Masue; Mitsui, Tetsuo; Hori, Hiroki; Hara, Junichi; Horibe, Keizo; Nagai, Jun-ichi; Goto, Hiroaki; Ito, Etsuro

2014-11-01

213

A physical map, including a BAC/PAC clone contig, of the Williams-Beuren syndrome--deletion region at 7q11.23.  

PubMed

Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although >/=16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of >/=320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region. PMID:10631136

Peoples, R; Franke, Y; Wang, Y K; Pérez-Jurado, L; Paperna, T; Cisco, M; Francke, U

2000-01-01

214

Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus.  

PubMed

The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus. PMID:23832106

Sakai, Yasunari; Ohkubo, Kazuhiro; Matsushita, Yuki; Akamine, Satoshi; Ishizaki, Yoshito; Torisu, Hiroyuki; Ihara, Kenji; Sanefuji, Masafumi; Kim, Min-Seon; Lee, Ki-Up; Shaw, Chad A; Lim, Janghoo; Nakabeppu, Yusaku; Hara, Toshiro

2013-09-01

215

Deletion of hepatocyte nuclear factor-1-beta in an infant with prune belly syndrome.  

PubMed

Prune belly syndrome is a rare congenital disorder characterized by deficiency of abdominal wall muscles, cryptorchidism, and urinary tract anomalies. We have had the opportunity to study a baby with prune belly syndrome associated with an apparently de novo 1.3-megabase interstitial 17q12 microdeletion that includes the hepatocyte nuclear factor-1-beta gene at 17q12. One previous patient, an adult, has been reported with prune belly syndrome and a hepatocyte nuclear factor-1-beta microdeletion. Hepatocyte nuclear factor-1-beta is a widely expressed transcription factor that regulates tissue-specific gene expression and is expressed in numerous tissues including mesonephric duct derivatives, the renal tubule of the metanephros, and the developing prostate of the mouse. Mutations in hepatocyte nuclear factor-1-beta cause the "renal cysts and diabetes syndrome," isolated renal cystic dysplasia, and a variety of other malformations. Based on its expression pattern and the observation of two affected cases, we propose that haploinsufficiency of hepatocyte nuclear factor-1-beta may be causally related to the production of the prune belly syndrome phenotype through a mechanism of prostatic and ureteral hypoplasia that results in severe obstructive uropathy with urinary tract and abdominal distension. PMID:20175044

Haeri, Sina; Devers, Patricia L; Kaiser-Rogers, Kathleen A; Moylan, Vincent J; Torchia, Beth S; Horton, Amanda L; Wolfe, Honor M; Aylsworth, Arthur S

2010-08-01

216

The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy  

SciTech Connect

Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

Mezghani, Najla [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)] [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Mnif, Mouna [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia)] [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Mkaouar-Rebai, Emna, E-mail: emna_mkaouar@mail2world.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)] [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Kallel, Nozha [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia)] [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Salem, Ikhlass Haj [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)] [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Charfi, Nadia; Abid, Mohamed [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia)] [Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)] [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

2011-07-29

217

Psychiatric Disorders and Intellectual Functioning throughout Development in Velocardiofacial (22q11.2 Deletion) Syndrome  

ERIC Educational Resources Information Center

Objective: Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample.…

Green, Tamar; Gothelf, Doron; Glaser, Bronwyn; Debbane, Martin; Frisch, Amos; Kotler, Moshe; Weizman, Abraham; Eliez, Stephan

2009-01-01

218

Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome.  

PubMed

Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations. PMID:25434003

Wieczorek, Dagmar; Newman, William G; Wieland, Thomas; Berulava, Tea; Kaffe, Maria; Falkenstein, Daniela; Beetz, Christian; Graf, Elisabeth; Schwarzmayr, Thomas; Douzgou, Sofia; Clayton-Smith, Jill; Daly, Sarah B; Williams, Simon G; Bhaskar, Sanjeev S; Urquhart, Jill E; Anderson, Beverley; O'Sullivan, James; Boute, Odile; Gundlach, Jasmin; Czeschik, Johanna Christina; van Essen, Anthonie J; Hazan, Filiz; Park, Sarah; Hing, Anne; Kuechler, Alma; Lohmann, Dietmar R; Ludwig, Kerstin U; Mangold, Elisabeth; Steenpaß, Laura; Zeschnigk, Michael; Lemke, Johannes R; Lourenco, Charles Marques; Hehr, Ute; Prott, Eva-Christina; Waldenberger, Melanie; Böhmer, Anne C; Horsthemke, Bernhard; O'Keefe, Raymond T; Meitinger, Thomas; Burn, John; Lüdecke, Hermann-Josef; Strom, Tim M

2014-12-01

219

The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome.  

PubMed

Tests for allelism among mice with four different mutant alleles at the shaker-with-syndactylism locus on mouse Chromosome (Chr) 18 provide evidence that the original radiation-induced mutation, sy, is a deletion including at least two genes associated with distinct phenotypes. Mice homozygous for sy have syndactylous feet and other skeletal malformations, are deaf, and exhibit abnormal behavior characteristic of vestibular dysfunction. Two less severe spontaneous mutations, shown to be allelic with sy, cause syndactylism when homozygous (hence named fused phalanges, sy(fp) and sy(fp-2J)), but do not affect hearing and behavior. Here we describe a third spontaneous mutation allelic with sy that does not affect foot morphology (hence named no syndactylism, sy(ns)), but that does cause deafness and balance defects when homozygous. Complementation test results indicate that sy(fp) and sy(fp-2J) are alleles of the same gene, but that sy(ns) is an allele of a different gene. The original sy mutation, therefore, includes both of the genes defined by these three spontaneous mutations. Typing of DNA markers in sy/sy mice revealed a deletion of approximately 1 cM in the sy region of Chr 18, including D18Mit52, D18Mit124, D18Mit181, and D18Mit205. The genetic relationships described here will aid in positional cloning efforts to identify the genes responsible for the disparate phenotypes associated with the sy locus. PMID:9799839

Johnson, K R; Cook, S A; Zheng, Q Y

1998-11-01

220

A new microduplication syndrome encompassing the region of the Miller–Dieker (17p13 deletion) syndrome  

Microsoft Academic Search

Background:The use of array comparative genome hybridisation (CGH) analyses for investigation of children with mental retardation has led to the identification of a growing number of new microdeletion and microduplication syndromes, some of which have become clinically well characterised and some that await further delineation. This report describes three children with de novo 17p13.1 duplications encompassing the PAFAH1B1 gene, who

L Roos; A E Jønch; S Kjaergaard; K Taudorf; H Simonsen; B Hamborg-Petersen; K Brøndum-Nielsen; M Kirchhoff

2009-01-01

221

UBE2A deficiency syndrome: A report of two unrelated cases with large Xq24 deletions encompassing UBE2A gene.  

PubMed

Intragenic mutations of the UBE2A gene, as well as larger deletions of Xq24 encompassing UBE2A have in recent years been associated with a syndromic form of X-linked intellectual disability called UBE2A deficiency syndrome or X-linked intellectual disability type Nascimento (OMIM#300860). Common clinical features in these patients include moderate to severe intellectual disability (ID), heart defects, dysmorphic features such as high forehead, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, wide mouth, myxedematous appearance, hirsutism, onychodystrophy, and genital anomalies. This study investigates clinical and molecular data of two unrelated, affected males with chromosome Xq24 deletions encompassing UBE2A. Both have been followed from birth until two years of age. A review of the previously published patients with deletions encompassing UBE2A is provided. Besides the common features, the two boys show anomalies not previously described, such as retinal coloboma, esophageal atresia with esophageal fistula, long fingers, camptodactyly, clinodactyly, and long broad toes. Analyses of the phenotype-genotype correlations suggest considerable prevalence of heart defects in the group of patients with larger deletions of Xq24 in comparison to the patients having intragenic UBE2A mutations. However, further studies are needed in order to establish statistically reliable phenotype-genotype correlations of this syndrome. © 2014 Wiley Periodicals, Inc. PMID:25287747

Thunstrom, Sofia; Sodermark, Liv; Ivarsson, Liz; Samuelsson, Lena; Stefanova, Margarita

2015-01-01

222

Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome.  

PubMed Central

Three families are reported who have a translocation involving 4p16.3. Nine subjects are described with the clinical features of the Pitt-Rogers-Danks (PRD) syndrome confirming pre- and postnatal growth failure, microcephaly, severe mental retardation, seizures, and a distinctive facial appearance; a deletion of 4p16.3 was seen in all eight patients studied with fluorescence in situ hybridisation (FISH). Eleven subjects had a new syndrome with physical overgrowth, heavy facial features, and mild to moderate mental handicap; a duplication of the chromosome region 4p16.3 was found in the four subjects studied. It is suggested that the growth abnormalities in these two families may be explained by a dosage effect of the fibroblast growth factor receptor gene 3 (FGFR3), which is located at 4p16.3, that is, a single dose leads to growth failure and a triple dose to physical overgrowth. We describe the molecular mapping of the translocation breakpoint and define it to within locus D4S43. Images PMID:9321756

Partington, M W; Fagan, K; Soubjaki, V; Turner, G

1997-01-01

223

Structural chromosomal abnormalities detected during CVS analysis and their role in the prenatal ascertainment of cryptic subtelomeric rearrangements.  

PubMed

Mosaic structural chromosomal abnormalities observed along the trophoblast-mesenchyme-fetal axis, although rare, pose a difficult problem for their prognostic interpretation in prenatal diagnosis. Additional issues are raised by the presence of mosaic imbalances of the same chromosome showing different sizes in the different tissues, that is, deletions and duplications in the cytotrophoblast and mesenchyme of chorionic villi (CV). Some of these cytogenetic rearrangements originate from the post-zygotic breakage of a dicentric chromosome or of the product of its first anaphasic breakage. Selection of the most viable cell line may result in confined placental mosaicism of the most severe imbalance, favoring the presence of the cell lines with the mildest duplications or deletions in the fetal tissues. We document three cases of ambiguous results in CV analysis due to the presence of different cell lines involving structural rearrangements of the same chromosome which were represented differently in the trophoblast and the mesenchyme. Observation by conventional karyotype of a grossly rearranged chromosome in one of the CV preparations (direct or culture) was crucial to call attention to the involved chromosomal region in other tissues (villi or amniotic fluid), allowing the prenatal diagnosis through molecular cytogenetic methods of subtelomeric rearrangements [del(7)(q36qter); del(11)(q25qter); del(20)(p13pter)]. This would have surely been undiagnosed with the routine banding technique. In conclusion, the possibility to diagnose complex abnormalities leading to cryptic subtelomeric rearrangements, together with a better knowledge of the initial/intermediate products leading to the final abnormal cryptic deletion should be added to the advantages of the CV sampling technique. PMID:23922197

Pittalis, Maria Carla; Mattarozzi, Angela; Menozzi, Cristina; Malacarne, Michela; Baccolini, Ilaria; Farina, Antonio; Pompilii, Eva; Magini, Pamela; Percesepe, Antonio

2013-10-01

224

A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13  

SciTech Connect

We report on a 5-year-old white girl with Prader-Willi syndrome (PWS) and a submicroscopic deletion of 15q11q13 of approximately 100-200 kb in size. High resolution chromosome analysis was normal but fluorescence in situ hybridization (FISH), Southern hybridization, and microsatellite data from the 15q11q13 region demonstrated that the deletion was paternal in origin and included the SNRPN, PAR-5, and PAR-7 genes from the proximal to distal boundaries of the deletion segment. SNRPN and PW71B methylation studies showed an abnormal pattern consistent with the diagnosis of PWS and supported the presence of a paternal deletion of 15q11q13 or an imprinting mutation. Biparental (normal) inheritance of PW71B (D15S63 locus) and a deletion of the SNRPN gene were observed by microsatellite, quantitative Southern hybridization, and/or FISH analyses. Our patient met the diagnostic criteria for PWS, but has no reported behavior problems, hyperphagia, or hypopigmentation. Our patient further supports SNRPN and possibly other genomic sequences which are deleted as the cause of the phenotype recognized in PWS patients. 21 refs., 7 figs.

Butler, M.G. [Vanderbilt Univ. Medical Center, Nashville, TN (United States)] [Vanderbilt Univ. Medical Center, Nashville, TN (United States); Christian, S.L.; Kubota, T.; Ledbetter, D.H. [National Inst. of Health, Bethesda, MD (United States)] [National Inst. of Health, Bethesda, MD (United States)

1996-10-16

225

Deletion of UBE3A in brothers with Angelman syndrome at the breakpoint with an inversion at 15q11.2.  

PubMed

Angelman syndrome (AS) is characterized by severe intellectual disability with ataxia, epilepsy, and behavioral uniqueness. The underlining molecular deficit is the absence of the maternal copy of the imprinted UBE3A gene due to maternal deletions, which is observed in 70-75% of cases, and can be detected using fluorescent in situ hybridization (FISH) of the UBE3A region. Only a few familial AS cases have been reported with a complete deletion of UBE3A. Here, we report on siblings with AS caused by a microdeletion of 15q11.2-q12 encompassing UBE3A at the breakpoint of an inversion at 15q11.2 and 15q26.1. Karyotyping revealed an inversion of 15q, and FISH revealed the deletion of the UBE3A region. Array comparative genomic hybridization (CGH) demonstrated a 467?kb deletion at 15q11.2-q12, encompassing only UBE3A, SNORD115, and PAR1, and a 53?kb deletion at 15q26.1, encompassing a part of SLCO3A1. Their mother had a normal karyotype and array CGH detected no deletion of 15q11.2-q12, so we assumed gonadal mosaicism. This report describes a rare type of familial AS detected using the D15S10 FISH test. PMID:25099823

Kuroda, Yukiko; Ohashi, Ikuko; Saito, Toshiyuki; Nagai, Jun-Ichi; Ida, Kazumi; Naruto, Takuya; Wada, Takahito; Kurosawa, Kenji

2014-11-01

226

Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.  

PubMed

15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n?=?83) were compared with frequencies in the non-deleted cohort (n?=?14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR?=?6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc. PMID:24715682

Cafferkey, Michiala; Ahn, Joo Wook; Flinter, Frances; Ogilvie, Caroline

2014-08-01

227

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome  

PubMed Central

Angelman syndrome (AS) is a severe neurobehavioural disorder caused by failure of expression of the maternal copy of the imprinted domain located on 15q11-q13. There are different mechanisms leading to AS: maternal microdeletion, uniparental disomy, defects in a putative imprinting centre, mutations of the E3 ubiquitin protein ligase (UBE3A) gene. However, some of suspected cases of AS are still scored negative to all the latter mutations. Recently, it has been shown that a proportion of negative cases bear large deletions overlapping one or more exons of the UBE3A gene. These deletions are difficult to detect by conventional gene-scanning methods due to the masking effect by the non-deleted allele. In this study, we have used for the first time multiplex ligation-dependent probe amplification (MLPA) and comparative multiplex dosage analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients. PMID:21072004

Calì, Francesco; Ragalmuto, Alda; Chiavetta, Valeria; Calabrese, Giuseppe; Fichera, Marco; Vinci, Mirella; Ruggeri, Giuseppa; Schinocca, Pietro; Sturnio, Maurizio; Romano, Salvatore; Elia, Maurizio

2010-01-01

228

Functional Gene-Expression Analysis Shows Involvement of Schizophrenia-Relevant Pathways in Patients with 22q11 Deletion Syndrome  

PubMed Central

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable. PMID:22457764

van Beveren, Nico J. M.; Krab, Lianne C.; Swagemakers, Sigrid; Buitendijk, Gabriella; Boot, Erik; van der Spek, Peter; Elgersma, Ype; van Amelsvoort, Therese A. M. J.

2012-01-01

229

Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome.  

PubMed

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable. PMID:22457764

van Beveren, Nico J M; Krab, Lianne C; Swagemakers, Sigrid; Buitendijk, Gabriella; Buitendijk, Gabriëlle H S; Boot, Erik; van der Spek, Peter; Elgersma, Ype; van Amelsvoort, Therese A M J

2012-01-01

230

White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging  

PubMed Central

Children with chromosome 22q11.2 Deletion Syndrome (22q11.2DS), Fragile X Syndrome (FXS), or Turner Syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14 years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders. PMID:23602925

Villalon, Julio; Jahanshad, Neda; Beaton, Elliott; Toga, Arthur W.; Thompson, Paul M.; Simon, Tony J.

2014-01-01

231

In Saccharomyces cerevisiae, yKu and Subtelomeric Core X Sequences Repress Homologous Recombination Near Telomeres as Part of the Same Pathway  

PubMed Central

Unlike in meiosis where recombination near telomeres is repressed, subtelomeric regions appear to recombine with each other frequently in vegetative cells with no detrimental consequences. To test whether or not such recombination is prevented in the core of chromosomes for maintenance of genome stability, we measured allelic homologous recombination (HR) along chromosome arms and between different ectopic locations. We found that there is an increase of recombination at telomeres in wild-type cells compared with sequences at proximal subtelomeric and interstitial regions of the genome. We also screened for mutations that result in an increase in HR between a telomeric sequence and a more internal sequence, which normally exhibit very low rates of HR. YKU80 was hit most frequently in our screen, and we show that the yKu heterodimer specifically represses HR in the vicinity of telomeres. This repression of HR is not explained solely by the role of yKu in maintaining telomere length, silencing, or tethering to the nuclear periphery. Analysis of mutant strains harboring deleted core X sequences revealed a role for this subtelomeric element in preventing telomeric recombination. Furthermore, core X bestowed this protection as part of the same pathway as yKu. Our findings implicate a role for both yKu and core X in stabilizing the genome against recombination events involving telomeric sequences. PMID:19652177

Marvin, Marcus E.; Griffin, Craig D.; Eyre, David E.; Barton, David B. H.; Louis, Edward J.

2009-01-01

232

Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions on the short arm of chromosome 11  

SciTech Connect

A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of {approximately}20 cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalia permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region. 31 refs., 5 figs., 1 tab.

Bartsch, O.; Werner, W.; Hinkel, G.K. [Univ. Hospital Dresden (Germany); Van Hul, W.; Willems, P.J. [Univ. of Antwerp (Belgium)] [and others

1996-04-01

233

Molecular and cytogenetic analysis of familial Xp deletions  

SciTech Connect

Deletions involving the short arm of the X chromosome (del(Xp)) manifest phenotypes ranging from Turner syndrome to isolated short stature to normal. We have studied five familial cases of del(Xp), four with transmission over two generations and one over four generations, utilizing both high resolution chromosome banding and FISH with cosmid and YAC probes spanning the short arm of the X chromosome. Four of the families were ascertained because of short stature while the remaining family demonstrates normal stature and was ascertained through prenatal diagnosis. Consistent with existing data for a growth gene located within Xp22.33, the more terminal breakpoints in the female with normal stature is distal to CSF2RA. A correlation between genotype and phenotype amongst the families may reveal that this case is representative of an interstitial deletion and the other four cases have breakpoints distal to the growth gene locus possibly within the subtelomeric region of the chromosome. The proximal breakpoints are heterogenous; however, three of the families with short stature share a common proximal breakpoint which is located between two YAC probes 2-3 Mb apart in Xp22.12. The proximal break in the phenotypically normal female is in Xp11.4. Late replication studies in addition to methylation assays of the FMR1 locus reveal non-random X inactivation in these cases. This study shows the presence of a breakpoint distal to the CSF2RA locus in the family demonstrating normal stature confirming the location of a growth gene distal to this locus and within Xp22.33. The shared proximal breakpoint between the three families suggests a {open_quotes}hot spot{close_quotes} for chromatin breakage. The proximal breakpoint, Xp11.4, in the normal female patient excludes this region as an etiologic factor in Turner syndrome. Work is in progress using additional probes to further elucidate both the proximal and distal breakpoints.

Wandstrat, A.E.; Conroy, J.M.; Zurcher, V.L. [Case Western Reserve, Cleveland, OH (United States)] [and others

1994-09-01

234

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome.  

PubMed

AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.European Journal of Human Genetics advance online publication, 10 September 2014; doi:10.1038/ejhg.2014.173. PMID:25205402

Beunders, Gea; de Munnik, Sonja A; Van der Aa, Nathalie; Ceulemans, Berten; Voorhoeve, Els; Groffen, Alexander J; Nillesen, Willy M; Meijers-Heijboer, Elizabeth J; Kooy, R F; Yntema, Helger G; Sistermans, Erik A

2014-09-10

235

Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss  

PubMed Central

La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1Cre La-deleted mice produce no B cells. Consistent with ?CamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ?5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types. PMID:24190965

Gaidamakov, Sergei; Maximova, Olga A.; Chon, Hyongi; Blewett, Nathan H.; Wang, Hongsheng; Crawford, Amanda K.; Day, Amanda; Tulchin, Natalie; Crouch, Robert J.; Morse, Herbert C.; Blitzer, Robert D.

2014-01-01

236

Opposing phenotypes in mice with Smith-Magenis deletion and Potocki -Lupski duplication syndromes suggest gene dosage effects on fluid consumption behavior  

PubMed Central

A quantitative long-term fluid consumption and fluid licking assay was performed in two mouse models with either an ~ 2Mb genomic deletion, Df(11)17, or the reciprocal duplication CNV, Dp(11)17, analogous to the human genomic rearrangements causing either Smith-Magenis syndrome [SMS; OMIM #182290] or Potocki-Lupski syndrome [PTLS; OMIM #610883], respectively. Both mouse strains display distinct quantitative alteration in fluid consumption compared to their wild-type littermates; several of these changes are diametrically opposing between the two chromosome engineered mouse models. Mice with duplication vs. deletion showed longer vs. shorter intervals between visits to the waterspout, generated more vs. less licks per visit and had higher vs. lower variability in the number of licks per lick-burst as compared to their respective wild-type littermates. These findings suggest that copy number variation can affect long-term fluid consumption behavior in mice. Other behavior differences were unique for either the duplication or deletion mutants; the deletion CNV resulted in increased variability of the licking rhythm, and the duplication CNV resulted in a significant slowing of the licking rhythm. Our findings document a readily quantitated complex behavioral response that can be directly and reciprocally influenced by a gene dosage effect. PMID:22991245

Heck, Detlef H.; Gu, Wenli; Cao, Ying; Qi, Shuhua; Lacaria, Melanie; Lupski, James R.

2012-01-01

237

Identification of the WBSCR9 gene, encoding a novel transcriptional regulator, in the Williams-Beuren syndrome deletion at 7q11.23  

Microsoft Academic Search

We have identified a novel gene (WBSCR9) within the common Williams-Beuren syndrome (WBS) deletion by interspecies sequence conservation. The WBSCR9 gene encodes a roughly 7-kb transcript with an open reading frame of 1483 amino acids and a predicted protein product size of 170.8 kDa. WBSCR9 is comprised of at least 20 exons extending over 60 kb. The transcript is expressed

R. J. Peoples; M. J. Cisco; P. Kaplan; U. Francke

1998-01-01

238

Two families with isolated cat cry without the cri-du-chat syndrome phenotype have an inherited 5p15.3 deletion: Delineation of the larynx malformation region  

Microsoft Academic Search

The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth that is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on two families

M. Gersh; J. Overhauser; L. M. Pasztor

1994-01-01

239

Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q.  

PubMed Central

Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both. Images PMID:7562965

Van Camp, G; Van Thienen, M N; Handig, I; Van Roy, B; Rao, V S; Milunsky, A; Read, A P; Baldwin, C T; Farrer, L A; Bonduelle, M

1995-01-01

240

Assessment of Parental Disclosure of a 22q11.2 Deletion Syndrome Diagnosis and Implications for Clinicians  

PubMed Central

Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the disclosure of a 22q11DS diagnosis to the affected child, or the factors that influence parents’ disclosure to the child. A pilot study was conducted including eight semi-structured interviews with caregivers of children with 22q11DS, 10 to 17 years of age, to investigate the factors that influence how parents inform their children of the diagnosis. Six of eight participants had disclosed the diagnosis to the child, and most of these parents felt they could have benefited from additional advice from professionals to increase their confidence and success, as well as the child’s comprehension of the information. Those who had not informed the child were uncertain about the words to use, how to initiate the conversation, or were concerned about the child’s level of understanding. Our results demonstrate that genetics professionals should help prepare caregivers for conversations with their children about the diagnosis of 22q11DS, monitor the understanding of the diagnosis over time, and provide ongoing support. PMID:22936417

Faux, Dana; Eubanks, Sonja; Hooper, Stephen R.; Shashi, Vandana

2012-01-01

241

A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients  

PubMed Central

Objective Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0. Methods Patients from Children's Hospital of Philadelphia, USA and Wilhelmina Children's Hospital Utrecht, The Netherlands were stratified based on palatal phenotype (overt cleft, submucosal cleft, bifid uvula). SNPs in 21 candidate genes for cleft palate were analyzed for genotype-phenotype association. In addition, TBX1 sequencing was carried out. Quality control and association analyses were conducted using the software package PLINK. Results Genotype and phenotype data of 101 unrelated patients (63 non-cleft subjects (62.4%), 38 cleft subjects (37.6%)) were analyzed. A Total of 39 SNPs on 10 genes demonstrated a p-value ?0.05 prior to correction. The most significant SNPs were found on FGF10. However none of the SNPs remained significant after correcting for multiple testing. Conclusions Although these results are promising, analysis of additional samples will be required to confirm that variants in these regions influence risk for cleft palate or palatal anomalies in 22q11.2DS patients. PMID:23121717

Widdershoven, Josine C.C.; Bowser, Mark; Sheridan, Molly B.; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Solot, Cynthia B.; Kirschner, Richard E.; Beemer, Frits A.; Morrow, Bernice E.; Devoto, Marcella; Emanuel, Beverly S.

2014-01-01

242

The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion  

SciTech Connect

Williams syndrome (WS) is a developmental disorder with multiple system manifestations, including supraval var aortic stenosis (SVAS), peripheral pulmonic stenosis, connective tissue abnormalities, short stature, characteristic personality profile and cognitive deficits, and variable hypercalcemia in infancy. It is caused by heterozygosity for a chromosomal deletion of part of band 7q11.23 including the elastin locus (ELN). Since disruption of the ELN gene causes autosomal dominant SVAS, it is assumed that ELN haploinsufficiency is responsible for the cardiovascular features of WS. The deletion that extends from the ELN locus in both directions is {ge}200 kb in size, although estimates of {ge}2 Mb are suggested by high-resolution chromosome banding and physical mapping studies. We have searched for additional dosage-sensitive genes within the deletion that may be responsible for the noncardiovascular features. We report here that the gene for replication factor C subunit 2 (RFC2) maps within the WS deletion region and was found to be deleted in all of 18 WS patients studied. The protein product of RFC2 is part of a multimeric complex involved in DNA elongation during replication. 14 refs., 3 figs.

Peoples, R.; Perez-Jurado, L.; Francke, U.; Yu-Ker Wang [Stanford Univ. Medical Center, CA (United States); Kaplan, P. [Children`s Hospital of Philadelphia, PA (United States)

1996-06-01

243

A recurrent deletion syndrome at chromosome bands 2p11.2-2p12 flanked by segmental duplications at the breakpoints and including REEP1.  

PubMed

We identified an identical and recurrent 9.4-Mbp deletion at chromosome bands 2p11.2-2p12, which occurred de novo in two unrelated patients. It is flanked at the distal and proximal breakpoints by two homologous segmental duplications consisting of low copy repeat (LCR) blocks in direct orientation, which have >99% sequence identity. Despite the fact that the deletion was almost 10?Mbp in size, the patients showed a relatively mild clinical phenotype, that is, mild-to-moderate intellectual disability, a happy disposition, speech delay and delayed motor development. Their phenotype matches with that of previously described patients. The 2p11.2-2p12 deletion includes the REEP1 gene that is associated with spastic paraplegia and phenotypic features related to this are apparent in most 2p11.2-2p12 deletion patients, but not in all. Other hemizygous genes that may contribute to the clinical phenotype include LRRTM1 and CTNNA2. We propose a recurrent but rare 2p11.2-2p12 deletion syndrome based on (1) the identical, non-random localisation of the de novo deletion breakpoints in two unrelated patients and a patient from literature, (2) the patients' phenotypic similarity and their phenotypic overlap with other 2p deletions and (3) the presence of highly identical LCR blocks flanking both breakpoints, consistent with a non-allelic homologous recombination (NAHR)-mediated rearrangement.European Journal of Human Genetics advance online publication, 2 July 2014; doi:10.1038/ejhg.2014.124. PMID:24986827

Stevens, Servi J C; Blom, Eveline W; Siegelaer, Ingrid T J; Smeets, Eric E J G L

2014-07-01

244

A 2.84 Mb deletion at 21q22.11 in a patient clinically diagnosed with Marden-Walker syndrome.  

PubMed

We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244 k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84 Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11. PMID:23894067

Carrascosa-Romero, María Carmen; Suela, Javier; Pardal-Fernández, José Manuel; Bermejo-Sánchez, Eva; Vidal-Company, Alberto; MacDonald, Alexandra; Tébar-Gil, Roque; Martínez-Fernández, María Luisa; Martínez-Frías, María Luisa

2013-09-01

245

A child with an inherited 0.31?Mb microdeletion of chromosome 14q32.33: further delineation of a critical region for the 14q32 deletion syndrome.  

PubMed

Chromosome 14q32.3 deletions are uncommon, with most described patients harboring a ring chromosome 14. Only 15 deletions have been described not associated with ring formation or other complex chromosomal rearrangements. Here, we describe a child with the smallest deletion of chromosome 14q32.3 reported in the literature. This child's deletion encompasses at most 0.305?Mb and six genes including NUDT14, BRF1, BTBD6, PACS2, MTA1, and TEX22. He has similar clinical findings, including mild facial dysmorphisms and intellectual disability, as other individuals with much larger deletions of the terminus of the long arm of chromosome 14. This suggests that the genes deleted in our patient contribute to the 14q32 deletion syndrome. PMID:22488736

Holder, J Lloyd; Lotze, Timothy E; Bacino, Carlos; Cheung, Sau-Wai

2012-08-01

246

Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence  

PubMed Central

Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence. PMID:23644601

Thijssen, Peter E.; Tobi, Elmar W.; Balog, Judit; Schouten, Suzanne G.; Kremer, Dennis; El Bouazzaoui, Fatiha; Henneman, Peter; Putter, Hein; Eline Slagboom, P.; Heijmans, Bastiaan T.; Van der Maarel, Silvère M.

2013-01-01

247

Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome.  

PubMed

OBJECTIVE. Enteropathy is a very common feature in patients with primary immunodeficiencies. In patients with Del22 gastrointestinal (GI) alterations, including feeding disorders and congenital abnormalities have been often reported, mostly in the first year of life. MATERIAL AND METHODS. Aim of this monocentric study is to better define the GI involvement in a cohort of 26 patients affected with Del22 syndrome. Anamnestic information was retrospectively collected for each patient. Weight and height parameters at the time of the screening were recorded. Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured. RESULTS. A GI involvement was identified in the 58% of patients. The prominent problems were abdominal pain, vomiting, gastroesophageal reflux and chronic constipation. Weight deficiency, short stature and failure to thrive were reported in 54, 42, and 30% of the patients, respectively. The evidence of sideropenic anemia, in keeping with hypoproteinemia, impaired acid steatocrit or cellobiose/mannitol test suggested an abnormal intestinal permeability. In this cohort, a high prevalence of AGA IgA and IgG positivity was observed. Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology. In this patient, a long-lasting gluten-free diet failed to restore the intestinal architecture. CONCLUSIONS. In conclusion, GI involvement is a very common feature in Del22 patients. A better characterization of GI involvement would be very useful to improve the management of these patients. PMID:24344832

Giardino, Giuliana; Cirillo, Emilia; Maio, Filomena; Gallo, Vera; Esposito, Tiziana; Naddei, Roberta; Grasso, Fiorentino; Pignata, Claudio

2014-03-01

248

Deletions Involving Long-Range Conserved Nongenic Sequences Upstream and Downstream of FOXL2 as a Novel Disease-Causing Mechanism in Blepharophimosis Syndrome  

PubMed Central

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes. PMID:15962237

Beysen, D.; Raes, J.; Leroy, B. P.; Lucassen, A.; Yates, J. R. W.; Clayton-Smith, J.; Ilyina, H.; Brooks, S. Sklower; Christin-Maitre, S.; Fellous, M.; Fryns, J. P.; Kim, J. R.; Lapunzina, P.; Lemyre, E.; Meire, F.; Messiaen, L. M.; Oley, C.; Splitt, M.; Thomson, J.; Peer, Y. Van de; Veitia, R. A.; De Paepe, A.; De Baere, E.

2005-01-01

249

Chromosome breakage in Prader-Willi and Angelman syndrome deletions may involve recombination between a repeat at the proximal and distal breakpoints  

SciTech Connect

Prader-Willi (PWS) and Angelman (AS) syndromes most commonly arise from large deletions of 15q11-q13. Deletions in PWS are paternal in origin, while those in AS are maternal in origin, clearly demonstrating genomic imprinting in these clinically distinct neurobehavioural disorders. In at least 90% of PWS and AS deletion patients, the same 4 Mb region within 15q11-q13 is deleted with breakpoints clustering in single YAC clones at the proximal and distal ends. To study the mechanism of chromosome breakage in PWS and AS, we have previously isolated 25 independent clones from these three YACs using Alu-vector PCR. Four clones were selected that appear to detect a low copy repeat that is located in the proximal and distal breakpoint regions of chromosome 15q11-q13. Three clones detect the same 4 HindIII bands in genomic DNA, all from 15q11-q13, with differing intensities for the probes located at the proximal or distal breakpoints region, respectively. This suggests that these probes detect related members of a low-copy repeat at either location. Moreover, the 254RL2 probe detects a novel HindIII band in two unrelated PWS deletion patients, suggesting that this may represent a breakpoint fragment, with recombination occurring within a similar interval in both patients. A fourth clone, 318RL3 detects 5 bands in HindIII-digested genomic DNA, all from 15q11-q13. This YAC endclone itself is not deleted in PWS and AS deletion patients, as seen by an invariant strong band. Two other strong bands are variably intact or deleted in different PWS or AS deletion patients, suggesting a relationship of this sequence to the breakpoints. Moreover, PCR using 318RL3 primers from the distal 93C9 YAC led to the isolation of a related clone with 96% identity, demonstrating the existence of a low-copy repeat with members close to the proximal and distal breakpoints. Taken together, our data suggest a complex, low-copy repeat with members at both the proximal and distal boundaries.

Amos-Landgraf J.; Nicholls, R.D. [Case Western Reserve Univ., Cleveland, OH (United States); Gottlieb, W. [Univ. of Florida, Gainesville, FL (United States)] [and others

1994-09-01

250

Atypical developmental trajectory of functionally significant cortical areas in children with chromosome 22q11.2 deletion syndrome.  

PubMed

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder associated with neurocognitive impairments. This article focuses on the cortical gyrification changes that are associated with the genetic disorder in 6-15-year-old children with 22q11.2DS, when compared with a group of age-matched typically developing (TD) children. Local gyrification index (lGI; Schaer et al. [2008]: IEEE Trans Med Imaging 27:161-170) was used to characterize the cortical gyrification at each vertex of the pial surface. Vertex-wise statistical analysis of lGI differences between the two groups revealed cortical areas of significant reduction in cortical gyrification in children with 22q11.2DS, which were mainly distributed along the medial aspect of each hemisphere. To gain further insight into the developmental trajectory of the cortical gyrification, we examined age as a factor in lGI changes over the 6-15 years of development, within and across the two groups of children. Our primary results pertaining to the developmental trajectory of cortical gyrification revealed cortical regions where the change in lGI over the 6-15 years of age was significantly modulated by diagnosis, implying an atypical development of cortical gyrification in children with 22q11.2DS, when compared with the TD children. Significantly, these cortical areas included parietal structures that are associated, in typical individuals, with visuospatial, attentional, and numerical cognition tasks in which children with 22q11.2DS show impairments. PMID:21416559

Srivastava, Siddharth; Buonocore, Michael H; Simon, Tony J

2012-01-01

251

Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome  

PubMed Central

The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMTMet compared to COMTVal, and greater reduction in those with greater decline in verbal IQ over time. Leave- one-out multivariate pattern analysis (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders. PMID:20817203

Gothelf, Doron; Hoeft, Fumiko; Ueno, Takefumi; Sugiura, Lisa; Lee, Agatha D.; Thompson, Paul; Reiss, Allan L.

2010-01-01

252

Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11) deletion syndrome  

PubMed Central

ABSTRACT We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS. PMID:24357327

Karpinski, Beverly A.; Maynard, Thomas M.; Fralish, Matthew S.; Nuwayhid, Samer; Zohn, Irene E.; Moody, Sally A.; LaMantia, Anthony-S.

2014-01-01

253

A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region  

PubMed Central

Background The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. Methods We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. Results Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. Conclusions From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders. PMID:20678247

2010-01-01

254

Two families with isolated cat cry without the cri-du-chat syndrome phenotype have an inherited 5p15.3 deletion: Delineation of the larynx malformation region  

SciTech Connect

The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth that is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on two families in which the patients with 5p deletions have only the characteristic cat-like cry with normal to mildly delayed development. One family has three children with varying levels of developmental delay and a deletion of 5p15.3 that was inherited from the father. The second family has a mother and daughter both presenting with a cat-like cry and normal intelligence. A de novo deletion in a patient with isolated cat cry and mild developmental delay was also identified. The precise locations of the deletions in each family were determined by fluorescent in situ hybridization using lambda phage, cosmids, and YAC clones. Cryptic translocations and mosaicism were not detected in the parents transmitting the deletion. All of the deletion breakpoints map distal to the previously defined cri-du-chat critical region. A YAC contig has been constructed for the chromosomal region implicated in the larynx malformation. DNA clones mapping in this region will be useful diagnostic tools for delineating 5p deletions that result in the typical features of cri-du-chat syndrome with deletions that result in the isolated cat-like cry feature which is associated with a better prognosis.

Gersh, M.; Overhauser, J. [Thomas Jefferson Univ., Philadelphia, PA (United States); Pasztor, L.M. [Children`s Mercy Hospital, Kansas City, MO (United States)] [and others

1994-09-01

255

Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions.  

PubMed

Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions. PMID:24715852

Dubourg, C; Bonnet-Brilhault, F; Toutain, A; Mignot, C; Jacquette, A; Dieux, A; Gérard, M; Beaumont-Epinette, M-P; Julia, S; Isidor, B; Rossi, M; Odent, S; Bendavid, C; Barthélémy, C; Verloes, A; David, V

2014-02-01

256

Mapping Genetically Controlled Neural Circuits of Social Behavior and Visuo-Motor Integration by a Preliminary Examination of Atypical Deletions with Williams Syndrome  

PubMed Central

In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain. PMID:25105779

Hoeft, Fumiko; Dai, Li; Haas, Brian W.; Sheau, Kristen; Mimura, Masaru; Mills, Debra; Galaburda, Albert; Bellugi, Ursula

2014-01-01

257

Deletions of Yq11 associated with short stature and the Turner syndrome. Tentative mapping of a region associated with specific Turner stigmata to proximal interval 5.  

SciTech Connect

Turner syndrome is a complex human phenotype, commonly associated with a 45,X karyotype. Mapping the Turner phenotype is difficult since hidden mosaicisms, partial monosomy and complex rearrangements are present in many affected individuals. In addition, attempts to map the genes involved to the X chromosome have failed to yield a consistent localisation. An alternative approach to map and identify Turner genes is to study XY individuals, with sex chromosome abnormalities, who present with or without characteristic Turner stigmata. We report the analysis of 4 individuals with terminal deletions of Yq. The individuals were azoospermic males without phenotypic abnormalities (2 cases) and azoospermic males presenting with a specific subset of Turner stigmata (2 cases). Breakpoints in each of the cytogenetically detectable Yq deletions were mapped by Southern analysis and Y chromosome-specific sequence tagged sites (STS). Correlation between the patients phenotypes and the extent of their deletion indicate a critical region associated with specific Turner stigmata (cubitus valgus, shield chest, short fourth metacarpals) and growth retardation at Yq at proximal interval 5. These data provide evidence that the somatic features of the Turner syndrome are most likely caused by haploinsufficiency of genes at several loci.

McElreavey, K.; Barbaux, S.; Vilain, E. [Immunogenetique Humaine 25 rue du Dr. Roux, Paris (France)] [and others

1994-09-01

258

Review of Disrupted Sleep Patterns in Smith-Magenis Syndrome and Normal Melatonin Secretion in a Patient with an Atypical Interstitial 17p11.2 Deletion  

PubMed Central

Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body’s signal for nighttime darkness. Published reports of 24-hour melatonin secretion patterns in two independent SMS cohorts (US & France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion (?6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.1p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern. PMID:19530184

Boudreau, Eilis A.; Johnson, Kyle P.; Jackman, Angela R.; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, MaryPat; Chandrasekharappa, Settara C.; Lewy, Alfred J.; Smith, Ann C. M.; Magenis, R. Ellen

2009-01-01

259

Organization and Evolution of Subtelomeric Satellite Repeats in the Potato Genome  

PubMed Central

Subtelomeric domains immediately adjacent to telomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes. A common feature associated with subtelomeric regions in different eukaryotes is the presence of long arrays of tandemly repeated satellite sequences. However, studies on molecular organization and evolution of subtelomeric repeats are rare. We isolated two subtelomeric repeats, CL14 and CL34, from potato (Solanum tuberosum). The CL14 and CL34 repeats are organized as independent long arrays, up to 1-3 Mb, of 182 bp and 339 bp monomers, respectively. The CL14 and CL34 repeat arrays are directly connected with the telomeric repeats at some chromosomal ends. The CL14 repeat was detected at the subtelomeric regions among highly diverged Solanum species, including tomato (Solanum lycopersicum). In contrast, CL34 was only found in potato and its closely related species. Interestingly, the CL34 repeat array was always proximal to the telomeres when both CL14 and CL34 were found at the same chromosomal end. In addition, the CL34 repeat family showed more sequence variability among monomers compared with the CL14 repeat family. We conclude that the CL34 repeat family emerged recently from the subtelomeric regions of potato chromosomes and is rapidly evolving. These results provide further evidence that subtelomeric domains are among the most dynamic regions in eukaryotic genomes. PMID:22384321

Torres, Giovana A.; Gong, Zhiyun; Iovene, Marina; Hirsch, Cory D.; Buell, C. Robin; Bryan, Glenn J.; Novák, Petr; Macas, Ji?í; Jiang, Jiming

2011-01-01

260

Chromosome arm length and nuclear constraints determine the dynamic relationship of yeast subtelomeres.  

PubMed

Physical interactions between distinct chromosomal genomic loci are important for genomic functions including recombination and gene expression, but the mechanisms by which these interactions occur remain obscure. Using telomeric association as a model system, we analyzed here the in vivo organization of chromosome ends of haploid yeast cells during interphase. We separately labeled most of the 32 subtelomeres and analyzed their positions both in nuclear space and relative to three representative reference subtelomeres by high-throughput 3D microscopy and image processing. We show that subtelomeres are positioned nonrandomly at the nuclear periphery, depending on the genomic size of their chromosome arm, centromere attachment to the microtubule organizing center (spindle pole body, SPB), and the volume of the nucleolus. The distance of subtelomeres to the SPB increases consistently with chromosome arm length up to approximately 300 kb; for larger arms the influence of chromosome arm length is weaker, but the effect of the nucleolar volume is stronger. Distances between pairs of subtelomeres also exhibit arm-length dependence and suggest, together with dynamic tracking experiments, that potential associations between subtelomeres are unexpectedly infrequent and transient. Our results suggest that interactions between subtelomeres are nonspecific and instead governed by physical constraints, including chromosome structure, attachment to the SPB, and nuclear crowding. PMID:20080699

Therizols, Pierre; Duong, Tarn; Dujon, Bernard; Zimmer, Christophe; Fabre, Emmanuelle

2010-02-01

261

NF1 Microdeletion Syndrome: Refined FISH Characterization of Sporadic and Familial Deletions with Locus-Specific Probes  

PubMed Central

Summary Two familial and seven sporadic patients with neurofibromatosis 1—who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene—were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the ?0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes—BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS—were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8–3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions. PMID:10631140

Riva, Paola; Corrado, Lucia; Natacci, Federica; Castorina, Pierangela; Wu, Bai-Li; Schneider, Gretchen H.; Clementi, Maurizio; Tenconi, Romano; Korf, Bruce R.; Larizza, Lidia

2000-01-01

262

Somatic and germ-line mosaicism of deletion 15q11.2-q13 in a mother of dyzigotic twins with Angelman syndrome.  

PubMed

Angelman syndrome (AS, OMIM105830) is a neurogenetic disorder caused by different genetic mechanisms. Determining the genetic mechanism is essential to establish the recurrence risk and the accuracy of genetic/reproductive counseling. The majority of AS patients present with a deletion of the 15q11.2-q13 region on the maternally derived chromosome. The other genetic mechanisms are: paternal disomy of chromosome 15, imprinting center defects, and mutations in the ubiquitin-protein ligase E3A gene (UBE3A). Different recurrence risks are associated with each specific genetic mechanism involved. We report on the study of dizygotic twins with classic phenotypic AS due to deletion of the same maternally derived chromosome 15. The mother presented with hypopigmented macular lesions on the inner side of both arms. Fibroblast culture studies of the maternal hypopigmented skin areas from both arms showed mosaicism for a normal cell line and for a second cell line with a 15q11.2-q13 deletion. This family represents the first demonstrated case of maternal somatic and germ line mosaicism for 15q11.2-q13 deletion as the cause of AS. PMID:24311297

Sánchez, Javier; Fernández, Raquel; Madruga, Marcos; Bernabeu-Wittel, José; Antiñolo, Guillermo; Borrego, Salud

2014-02-01

263

Brachydactyly mental retardation syndrome in differential diagnosis of pseudopseudohypoparathyroidism.  

PubMed

Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes. PMID:23645122

Hac?hamdio?lu, Bülent; Arslan, Mutluay; Sar?, Erkan; Kurtçu, Kemal; Yesilkaya, Ediz

2013-01-01

264

Genomic analysis and pathogenic characteristics of Type 2 porcine reproductive and respiratory syndrome virus nsp2 deletion strains isolated in Korea.  

PubMed

Porcine reproductive and respiratory syndrome virus (PRRSV) is a globally ubiquitous swine virus that exhibits genetic and pathogenic heterogeneity among isolates. The present study was conducted to determine the complete genome sequence and pathogenicity of two Korean type 2 PRRSV nonstructural protein 2 (nsp2) deletion mutants, CA-2 and KNU-12-KJ4. The full-length genomes of CA-2 and KNU-12-KJ4 were determined to be 15,018 and 15,019 nucleotides in length, excluding the poly(A) tail, respectively, which were 393- or 392-nucleotide shorter than that of the type 2 NA prototype strain VR-2332 due to the presence of notable large deletions within the nsp2 gene. The genomes of CA-2 and KNU-12-KJ4 consisted of a 189- or 190-nucleotide 5' untranslated region (UTR), a 14,677-nucleotide protein-coding region, and a 151-nucleotide 3' UTR. Whole genome evaluation revealed that the nucleotide sequences of CA-2 and KNU-12-KJ4 are most similar to each other (10.7% sequence divergence), and then to the Korean strain CA-1 (11.3% sequence divergence) and the US strain MN184C (13.1% sequence divergence), respectively. To evaluate the in vitro immunity of nsp2 deletion variants, we sought to explore alteration of inflammatory cytokine and chemokine expression in PAM-pCD163 cells infected with each virus strain using quantitative real-time RT-PCR. Cytokine genes including IL-8, IL-10, and TNF-?, and chemokines such as MCP-1 and RANTES were found to be significantly elevated in nsp2 deletion virus-infected PAM cells. In contrast, expression of interferons (IFN-?, ?, and ?) and antiviral genes including ISG-15, -54, and -56 were unchanged or down-regulated in PAM cells infected with the nsp2 deletion mutants. Animal studies to assess the pathogenicity of nsp2 deletion PRRSVs demonstrated that both CA-2 and KNU-12-KJ4 strains notably produce weight loss in infected pigs. Furthermore, the nsp2 deletion mutants replicated well in pigs with significantly increased and prolonged viremia kinetics. Taken together, our results indicate that, among the three isolates, the outcome of in vitro and in vivo infection by CA-2 and KNU-12-KJ4 is comparable, suggesting that the large nsp2 deletion may be one of the viral genetic determinants contributing to PRRSV pathogenicity. PMID:24646599

Choi, Hwan-Won; Nam, Eeuri; Lee, Yoo Jin; Noh, Yun-Hee; Lee, Seung-Chul; Yoon, In-Joong; Kim, Hyun-Soo; Kang, Shien-Young; Choi, Young-Ki; Lee, Changhee

2014-06-01

265

A deletion 13q34/duplication 14q32.2-14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia.  

PubMed

During infancy, this 50-year-old man with a previously undiagnosed multiple congenital anomalies/intellectual disability (MCA/MR) syndrome had grossly symptomatic hypercalcemia and was (briefly) thought to have Williams syndrome. Results of studies with the cytogenetic methods of the 1960s and 1970s were apparently normal. He matured late, but is high-functioning and healthy. Over 50 years he remained a diagnostic enigma. Thus, it came as a surprise when recent high-resolution banding methods showed an abnormality of the terminal portion of 13q, determined on array-comparative genomic hybridization to constitute an unbalanced chromosome rearrangement with a 0.35?Mb loss of 13q34-ter and 7.67?Mb gain of 14q32.2q32.33 translocated to 13q34. This apparently de novo genomic abnormality must be presumed as the cause of this previously undescribed MCA/MR syndrome which, however, may remain a private syndrome in this family. Williams syndrome was ruled out, and presently it is not possible to ascribe this patient's severely symptomatic infantile hypercalcemia to any gene on the deleted or duplicated chromosome segments. This "case" does underscore the importance of re-studying previously obscure but evidently genetic conditions, of long-term follow-up and documentation of natural history, and of providing, at last, a causal explanation to the family. PMID:21595000

Pallister, Philip D; Pallister, Adam B; South, Sarah; Toydemir, Reha; Johnson, John P; Beischel, Linda; Opitz, John M

2011-04-01

266

A 3.7 Mb Deletion Encompassing ZEB2 Causes a Novel Polled and Multisystemic Syndrome in the Progeny of a Somatic Mosaic Bull  

PubMed Central

Polled and Multisystemic Syndrome (PMS) is a novel developmental disorder occurring in the progeny of a single bull. Its clinical spectrum includes polledness (complete agenesis of horns), facial dysmorphism, growth delay, chronic diarrhea, premature ovarian failure, and variable neurological and cardiac anomalies. PMS is also characterized by a deviation of the sex-ratio, suggesting male lethality during pregnancy. Using Mendelian error mapping and whole-genome sequencing, we identified a 3.7 Mb deletion on the paternal bovine chromosome 2 encompassing ARHGAP15, GTDC1 and ZEB2 genes. We then produced control and affected 90-day old fetuses to characterize this syndrome by histological and expression analyses. Compared to wild type individuals, affected animals showed a decreased expression of the three deleted genes. Based on a comparison with human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation. Finally sperm-FISH, embryo genotyping and analysis of reproduction records confirmed somatic mosaicism in the founder bull and male-specific lethality during the first third of gestation. In conclusion, we identified a novel locus involved in bovid horn ontogenesis and suggest that epithelial-to-mesenchymal transition plays a critical role in horn bud differentiation. We also provide new insights into the pathogenicity of ZEB2 loss of heterozygosity in bovine and humans and describe the first case of male-specific lethality associated with an autosomal locus in a non-murine mammalian species. This result sets PMS as a unique model to study sex-specific gene expression/regulation. PMID:23152852

Capitan, Aurélien; Allais-Bonnet, Aurélie; Pinton, Alain; Marquant-Le Guienne, Brigitte; Le Bourhis, Daniel; Grohs, Cécile; Bouet, Stéphan; Clément, Laëtitia; Salas-Cortes, Laura; Venot, Eric; Chaffaux, Stéphane; Weiss, Bernard; Delpeuch, Arnaud; Noé, Guy; Rossignol, Marie-Noëlle; Barbey, Sarah; Dozias, Dominique; Cobo, Emilie; Barasc, Harmonie; Auguste, Aurélie; Pannetier, Maëlle; Deloche, Marie-Christine; Lhuilier, Emeline; Bouchez, Olivier; Esquerré, Diane; Salin, Gérald; Klopp, Christophe; Donnadieu, Cécile; Chantry-Darmon, Céline; Hayes, Hélène; Gallard, Yves; Ponsart, Claire; Boichard, Didier; Pailhoux, Eric

2012-01-01

267

Self-Reported Speech Problems in Adolescents and Young Adults with 22q11.2 Deletion Syndrome: A Cross-Sectional Cohort Study  

PubMed Central

Background Speech problems are a common clinical feature of the 22q11.2 deletion syndrome. The objectives of this study were to inventory the speech history and current self-reported speech rating of adolescents and young adults, and examine the possible variables influencing the current speech ratings, including cleft palate, surgery, speech and language therapy, intelligence quotient, and age at assessment. Methods In this cross-sectional cohort study, 50 adolescents and young adults with the 22q11.2 deletion syndrome (ages, 12-26 years, 67% female) filled out questionnaires. A neuropsychologist administered an age-appropriate intelligence quotient test. The demographics, histories, and intelligence of patients with normal speech (speech rating=1) were compared to those of patients with different speech (speech rating>1). Results Of the 50 patients, a minority (26%) had a cleft palate, nearly half (46%) underwent a pharyngoplasty, and all (100%) had speech and language therapy. Poorer speech ratings were correlated with more years of speech and language therapy (Spearman's correlation= 0.418, P=0.004; 95% confidence interval, 0.145-0.632). Only 34% had normal speech ratings. The groups with normal and different speech were not significantly different with respect to the demographic variables; a history of cleft palate, surgery, or speech and language therapy; and the intelligence quotient. Conclusions All adolescents and young adults with the 22q11.2 deletion syndrome had undergone speech and language therapy, and nearly half of them underwent pharyngoplasty. Only 34% attained normal speech ratings. Those with poorer speech ratings had speech and language therapy for more years. PMID:25276637

Vorstman, Jacob AS; Kon, Moshe; Mink van der Molen, Aebele B

2014-01-01

268

The 30-Amino-Acid Deletion in the Nsp2 of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Emerging in China Is Not Related to Its Virulence?  

PubMed Central

During the past 2 years, an atypical clinical outbreak, caused by a highly pathogenic porcine reproductive and respiratory syndrome virus (PRRSV) with a unique 30-amino-acid deletion in its Nsp2-coding region, was pandemic in China. In this study, we generated four full-length infectious cDNA clones: a clone of the highly virulent PRRSV strain JXwn06 (pWSK-JXwn), a clone of the low-virulence PRRSV strain HB-1/3.9 (pWSK-HB-1/3.9), a chimeric clone in which the Nsp2 region containing the 30-amino-acid deletion was replaced by the corresponding region of the low-virulence PRRSV strain HB-1/3.9 (pWSK-JXwn-HB1nsp2), and a mutated HB-1/3.9 clone with the same deletion in Nsp2 as JXwn06 (pWSK-HB1-ND30). We also investigated the pathogenicities of the rescued viruses (designated RvJXwn, RvJXwn-HB1nsp2, RvHB-1/3.9, and RvHB1-ND30, respectively) in specific-pathogen-free piglets in order to determine the role of the 30-amino-acid deletion in the virulence of the highly pathogenic PRRSV. All the rescued viruses could replicate stably in MARC-145 cells. Our findings indicated that RvJXwn-HB1nsp2 retained high virulence for piglets, like RvJXwn and the parental virus JXwn06, although the survival time of piglets infected with RvJXwn-HB1nsp2 was obviously prolonged. RvHB1-ND30 exhibited low virulence for piglets, like RvHB-1/3.9 and the parental virus HB-1/3.9. Therefore, we conclude that the 30-amino-acid deletion is not related to the virulence of the highly pathogenic PRRSV emerging in China. PMID:19244318

Zhou, Lei; Zhang, Jialong; Zeng, Jingwen; Yin, Shuoyan; Li, Yanhua; Zheng, Linying; Guo, Xin; Ge, Xinna; Yang, Hanchun

2009-01-01

269

Prospective Control Abilities during Visuo-Manual Tracking in Children with 22q11.2 Deletion Syndrome Compared to Age- and IQ-Matched Controls  

ERIC Educational Resources Information Center

To examine whether children with a 22q11.2 Deletion syndrome (22q11.2DS) are able to use prospective control, 21 children with 22q11.2DS (mean age=9.6 [plus or minus] 1.9; mean FSIQ=73.05 [plus or minus] 10.2) and 21 control children (mean age=9.6 [plus or minus] 1.9; mean FSIQ=73.38 [plus or minus] 12.0) were asked to perform a visuo-manual…

Van Aken, Katrijn; Swillen, Ann; Beirinckx, Marc; Janssens, Luc; Caeyenberghs, Karen; Smits-Engelsman, Bouwien

2010-01-01

270

The subtelomeric region is important for chromosome recognition and pairing during meiosis  

PubMed Central

The process of meiosis results in the formation of haploid daughter cells, each of which inherit a half of the diploid parental cells' genetic material. The ordered association of homologues (identical chromosomes) is a critical prerequisite for a successful outcome of meiosis. Homologue recognition and pairing are initiated at the chromosome ends, which comprise the telomere dominated by generic repetitive sequences, and the adjacent subtelomeric region, which harbours chromosome-specific sequences. In many organisms telomeres are responsible for bringing the ends of the chromosomes close together during early meiosis, but little is known regarding the role of the subtelomeric region sequence during meiosis. Here, the observation of homologue pairing between a pair of Hordeum chilense chromosomes lacking the subtelomeric region on one chromosome arm indicates that the subtelomeric region is important for the process of homologous chromosome recognition and pairing. PMID:25270583

Calderón, María del Carmen; Rey, María-Dolores; Cabrera, Adoración; Prieto, Pilar

2014-01-01

271

Schizophrenia and chromosomal deletions  

SciTech Connect

Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

Lindsay, E.A.; Baldini, A. [Baylor College of Medicine, Houston, TX (United States); Morris, M. A. [Univ. of Geneva School of Medicine, NY (United States)] [and others

1995-06-01

272

Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1)  

PubMed Central

Background Arachnomelia syndrome is an autosomal recessive inherited disease in cattle. Affected calves die around birth and show malformations of the skeleton mainly affecting the legs, the spinal column and the skull. A number of arachnomelia syndrome affected Simmental calves were recently detected by a surveillance system of anomalies with a peak of more than 120 recorded cases in the year 2006. The causative mutation was previously mapped to a 9 cM-region on bovine chromosome 23. We herein report the fine-mapping and identification of the gene causing arachnomelia syndrome in Simmental cattle. Results By using a dense set of markers, the arachnomelia syndrome linked region could be refined to 1.5 cM harbouring three protein coding genes. Comparative sequencing of these genes revealed a two-bp-deletion in the bovine MOCS1 gene resulting in a frame-shift and a premature termination codon. We genotyped affected calves and their ancestors and found that all affected were homozygous for the deletion whereas all carriers were heterozygous. Furthermore, cattle from the same population, but not directly related to known carriers mostly showed the wild type genotype. Conclusions MOCS1 encodes two proteins that are involved in the first synthesis step of molybdenum cofactor. A non functional sulfite-oxydase, one of the enzymes requiring molybdenum cofactor, leads to a similar pathology in Brown Swiss cattle. In combination the perfect association of the mutation with the phenotype and the obvious disruption of protein translation provide strong evidence for the causality of the MOCS1 mutation. Our results are the first example for an oligogenic lethal inherited disease in cattle. Furthermore, they show the potential involvement of sulfite metabolism in aberrant bone development. PMID:21255426

2011-01-01

273

Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay.  

PubMed

The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ib? (GP1BB) but also the SEPT5 gene, located 5' to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIb? and SEPT5 proteins in the patient's platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealed impaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleeding episodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. PMID:21800012

Bartsch, Ingrid; Sandrock, Kirstin; Lanza, Francois; Nurden, Paquita; Hainmann, Ina; Pavlova, Anna; Greinacher, Andreas; Tacke, Uta; Barth, Michael; Busse, Anja; Oldenburg, Johannes; Bommer, Martin; Strahm, Brigitte; Superti-Furga, Andrea; Zieger, Barbara

2011-09-01

274

A familial Cri-du-Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis.  

PubMed

Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ? 26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family. PMID:24143197

Gu, Heng; Jiang, Jian-hui; Li, Jian-ying; Zhang, Ya-nan; Dong, Xing-sheng; Huang, Yang-yu; Son, Xin-ming; Lu, Xinyan; Chen, Zheng

2013-01-01

275

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis  

PubMed Central

Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ?26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family. PMID:24143197

Zhang, Ya-nan; Dong, Xing-sheng; Huang, Yang-yu; Son, Xin-ming; Lu, Xinyan; Chen, Zheng

2013-01-01

276

Molecular cytogenetic determination of a deletion/duplication of 1q that results in a trisomy 18 syndrome-like phenotype  

SciTech Connect

We report on an infant who presented at birth with some characteristics of trisomy 18 syndrome, including low birth weight, facial abnormalities, overlapping fingers, and congenital heart defects. On chromosome analysis, no additional chromosome 18 was observed and both chromosome 18 homologues appeared normal. However, a small piece of chromosomal material of unknown origin was detected at the tip of the long arm of chromosome 1. Fluorescence in situ hybridization (FISH) using whole chromosome 18 painting probes disclosed no additional hybridization at the telomere of 1q, suggesting that the material was derived from another chromosome. Further chromosome painting experiments suggested that the telomeric addition was of chromosome 1 origin. To identify subchromosomal regions involved in the rearrangement, additional FISH analyses were performed using single copy and repetitive DNA probes mapping different portions of chromosome 1. The analyses showed that probes mapping to 1q34-43 were duplicated in the derivative chromosome 1. In addition, a DNA probe mapping to 1q44 was found to be deleted from the derivative chromosome 1. Our composite analysis suggests that a deletion and a duplication of chromosome 1q can result in some of the clinical findings usually associated with trisomy 16 syndrome. These results demonstrate the usefulness of FISH analysis when karyotype analysis is not consistent with the clinical description. 23 refs., 3 figs., 2 tabs.

Mewar, R.; Harrison, W.; Weaver, D.D.; Palmer, C.; Davee, M.A.; Overhauser, J.

1994-08-15

277

Chromosome 20p inverted duplication deletion identified in a Thai female adult with mental retardation, obesity, chronic kidney disease and characteristic facial features.  

PubMed

We report on a 21-year-old Thai woman presenting with mental retardation, developmental delays, selective mutism, distinctive facial features, sensorineural hearing loss, single right kidney, uterine didelphys and obesity. A longitudinal clinical course beginning in childhood revealed excessive weight gain, poor language skills and poor school performance. Chronic kidney disease stage 4, with elevated blood pressure, was first noted in adulthood. Array comparative genomic hybridization detected a copy loss at 20p13 co-existing with a copy gain at 20p13-20p11.22. A conventional cytogenetic study revealed the complex structural rearrangement of chromosome 20 [der (20) dup (20) (p11.2p13) del (20) (p13.pter)]. A FISH analysis, using probes against duplication and deletion regions, confirmed that there was an inverted duplication of p11.2-p13 and a deletion in the subtelomere region. Previous reports have identified this cytogenetic characterization in a Caucasian boy. Therefore, this is the first reported case of chromosome 20p inverted duplication deletion syndrome in an adult from the Southeast Asian population group. PMID:23542666

Trachoo, Objoon; Assanatham, Montira; Jinawath, Natini; Nongnuch, Arkom

2013-06-01

278

TBX1 Mutation Identified by Exome Sequencing in a Japanese Family with 22q11.2 Deletion Syndrome-Like Craniofacial Features and Hypocalcemia  

PubMed Central

Background Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS)-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. Methodology/Principal Findings We studied three subjects with craniofacial features and hypocalcemia (group 1), two subjects with craniofacial features alone (group 2), and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459) specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. Conclusions/Significance Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes. PMID:24637876

Kawai, Masahiko; Nagashima, Takeshi; Funayama, Ryo; Nakayama, Keiko; Nakashima, Shinichi; Kato, Fumiko; Fukami, Maki; Aoki, Yoko; Matsubara, Yoichi

2014-01-01

279

Longitudinal Follow-up of Autism Spectrum Features and Sensory Behaviors in Angelman Syndrome by Deletion Class  

ERIC Educational Resources Information Center

Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a "syndromic" form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (approximately 6 Mb) Class…

Peters, Sarika U.; Horowitz, Lucia; Barbieri-Welge, Rene; Taylor, Julie Lounds; Hundley, Rachel J.

2012-01-01

280

Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.  

PubMed

We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses. PMID:25118007

Loupe, Jacob; Sampath, Srirangan; Lacassie, Yves

2014-10-01

281

A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX.  

PubMed

Pierre Robin sequence (PRS) is an aetiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ?2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism. PMID:25195018

Ansari, Morad; Rainger, Jacqueline K; Murray, Jennie E; Hanson, Isabel; Firth, Helen V; Mehendale, Felicity; Amiel, Jeanne; Gordon, Christopher T; Percesepe, Antonio; Mazzanti, Laura; Fryer, Alan; Ferrari, Paola; Devriendt, Koenraad; Temple, I Karen; FitzPatrick, David R

2014-10-01

282

Autism Spectrum Disorders and Symptoms in Children with Molecularly Confirmed 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

In this study, we assessed the presence of autism spectrum disorders (ASD) among children with a confirmed 22q11.2 deletion (n = 98). The children's caregivers completed screening measures of ASD behaviors, and for those whose scores indicated significant levels of these behaviors, a standardized diagnostic interview (Autism Diagnostic…

Fine, Sarah E.; Weissman, Alison; Gerdes, Marsha; Pinto-Martin, Jennifer; Zackai, Elaine H.; McDonald-McGinn, Donna M.; Emanuel, Beverly S.

2005-01-01

283

Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome  

PubMed Central

Van den Ende-Gupta syndrome (VDEGS) is a congenital condition characterized by craniofacial and skeletal manifestations, specifically blepharophimosis, malar and maxillary hypoplasia, distinctive nose, arachnocamptodactyly, and long slender bones of the hands and feet. To date, only 24 patients have been described. It is generally thought that the syndrome is transmitted by an autosomal recessive mode of inheritance, although evidence for genetic heterogeneity has recently been presented. We report on a girl followed from birth up to 3 years of life with a set of peculiar minor anomalies, arachnocamptodactyly of hands and feet, characteristic of VDEGS in association with a 22q11.12 deletion. Recently, the VDEGS gene was mapped to the DiGeorge syndrome region on 22q11.2, and homozygous mutations in the SCARF2 gene were identified. We now report the first patient with VDEGS due to compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 splice site mutation. PMID:22140376

Bedeschi, M.F.; Colombo, L.; Mari, F.; Hofmann, K.; Rauch, A.; Gentilin, B.; Renieri, A.; Clerici, D.

2011-01-01

284

Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus  

PubMed Central

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3? AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future. PMID:23332918

Beunders, Gea; Voorhoeve, Els; Golzio, Christelle; Pardo, Luba M.; Rosenfeld, Jill A.; Talkowski, Michael E.; Simonic, Ingrid; Lionel, Anath C.; Vergult, Sarah; Pyatt, Robert E.; van de Kamp, Jiddeke; Nieuwint, Aggie; Weiss, Marjan M.; Rizzu, Patrizia; Verwer, Lucilla E.N.I.; van Spaendonk, Rosalina M.L.; Shen, Yiping; Wu, Bai-lin; Yu, Tingting; Yu, Yongguo; Chiang, Colby; Gusella, James F.; Lindgren, Amelia M.; Morton, Cynthia C.; van Binsbergen, Ellen; Bulk, Saskia; van Rossem, Els; Vanakker, Olivier; Armstrong, Ruth; Park, Soo-Mi; Greenhalgh, Lynn; Maye, Una; Neill, Nicholas J.; Abbott, Kristin M.; Sell, Susan; Ladda, Roger; Farber, Darren M.; Bader, Patricia I.; Cushing, Tom; Drautz, Joanne M.; Konczal, Laura; Nash, Patricia; de Los Reyes, Emily; Carter, Melissa T.; Hopkins, Elizabeth; Marshall, Christian R.; Osborne, Lucy R.; Gripp, Karen W.; Thrush, Devon Lamb; Hashimoto, Sayaka; Gastier-Foster, Julie M.; Astbury, Caroline; Ylstra, Bauke; Meijers-Heijboer, Hanne; Posthuma, Danielle; Menten, Björn; Mortier, Geert; Scherer, Stephen W.; Eichler, Evan E.; Girirajan, Santhosh; Katsanis, Nicholas; Groffen, Alexander J.; Sistermans, Erik A.

2013-01-01

285

A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection  

PubMed Central

The contribution of human subtelomeric DNA and chromatin organization to telomere integrity and chromosome end protection is not yet understood in molecular detail. Here, we show by ChIP-Seq that most human subtelomeres contain a CTCF- and cohesin-binding site within ?1–2?kb of the TTAGGG repeat tract and adjacent to a CpG-islands implicated in TERRA transcription control. ChIP-Seq also revealed that RNA polymerase II (RNAPII) was enriched at sites adjacent to the CTCF sites and extending towards the telomere repeat tracts. Mutation of CTCF-binding sites in plasmid-borne promoters reduced transcriptional activity in an orientation-dependent manner. Depletion of CTCF by shRNA led to a decrease in TERRA transcription, and a loss of cohesin and RNAPII binding to the subtelomeres. Depletion of either CTCF or cohesin subunit Rad21 caused telomere-induced DNA damage foci (TIF) formation, and destabilized TRF1 and TRF2 binding to the TTAGGG proximal subtelomere DNA. These findings indicate that CTCF and cohesin are integral components of most human subtelomeres, and important for the regulation of TERRA transcription and telomere end protection. PMID:23010778

Deng, Zhong; Wang, Zhuo; Stong, Nick; Plasschaert, Robert; Moczan, Aliah; Chen, Horng-Shen; Hu, Sufeng; Wikramasinghe, Priyankara; Davuluri, Ramana V; Bartolomei, Marisa S; Riethman, Harold; Lieberman, Paul M

2012-01-01

286

Autism Spectrum Disorders and Symptoms in Children with Molecularly Confirmed 22q11.2 Deletion Syndrome  

Microsoft Academic Search

In this study, we assessed the presence of autism spectrum disorders (ASD) among children with a confirmed 22q11.2 deletion (n = 98). The children’s caregivers completed screening measures of ASD behaviors, and for those whose scores indicated significant levels of these behaviors, a standardized diagnostic interview (Autism Diagnostic Interview-Revised; ADI-R) was administered. Results demonstrated that over 20% of children (n = 22) were exhibiting

Sarah E. Fine; Alison Weissman; Marsha Gerdes; Jennifer Pinto-Martin; Elaine H. Zackai; Donna M. McDonald-McGinn; Beverly S. Emanuel

2005-01-01

287

A 600?kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders  

PubMed Central

Background The recurrent ?600?kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases. PMID:23054248

Zufferey, Flore; Sherr, Elliott H; Beckmann, Noam D; Hanson, Ellen; Maillard, Anne M; Hippolyte, Loyse; Macé, Aurélien; Ferrari, Carina; Kutalik, Zoltán; Andrieux, Joris; Aylward, Elizabeth; Barker, Mandy; Bernier, Raphael; Bouquillon, Sonia; Conus, Philippe; Delobel, Bruno; Faucett, W Andrew; Goin-Kochel, Robin P; Grant, Ellen; Harewood, Louise; Hunter, Jill V; Lebon, Sébastien; Ledbetter, David H; Martin, Christa Lese; Männik, Katrin; Martinet, Danielle; Mukherjee, Pratik; Ramocki, Melissa B; Spence, Sarah J; Steinman, Kyle J; Tjernagel, Jennifer; Spiro, John E; Reymond, Alexandre; Beckmann, Jacques S; Chung, Wendy K; Jacquemont, Sébastien

2012-01-01

288

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.  

PubMed

Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS. PMID:25325218

Radoeva, Petya D; Coman, Ioana L; Salazar, Cynthia A; Gentile, Karen L; Higgins, Anne Marie; Middleton, Frank A; Antshel, Kevin M; Fremont, Wanda; Shprintzen, Robert J; Morrow, Bernice E; Kates, Wendy R

2014-12-01

289

Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.  

PubMed

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37. It is characterized by skeletal abnormalities and developmental delay. Here, we report on a girl who had phenotypes of both PH1 and BDMR. PCR-sequencing of the coding regions of AGXT showed a novel missense mutation, c.32C>G (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q. PMID:22821680

Tammachote, Rachaneekorn; Kingsuwannapong, Nelawat; Tongkobpetch, Siraprapa; Srichomthong, Chalurmpon; Yeetong, Patra; Kingwatanakul, Pornchai; Monico, Carla G; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

2012-09-01

290

Paracentric inversion of chromosome 2 associated with cryptic duplication of 2q14 and deletion of 2q37 in a patient with autism.  

PubMed

We describe a patient with autism and a paracentric inversion of chromosome 2q14.2q37.3, with a concurrent duplication of the proximal breakpoint at 2q14.1q14.2 and a deletion of the distal breakpoint at 2q37.3. The abnormality was derived from his mother with a balanced paracentric inversion. The inversion in the child appeared to be cytogenetically balanced but subtelomere FISH revealed a cryptic deletion at the 2q37.3 breakpoint. High-resolution single nucleotide polymorphism array confirmed the presence of a 3.5 Mb deletion that extended to the telomere, and showed a 4.2 Mb duplication at 2q14.1q14.2. FISH studies using a 2q14.2 probe showed that the duplicated segment was located at the telomeric end of chromosome 2q. This recombinant probably resulted from breakage of a dicentric chromosome. The child had autism, mental retardation, speech and language delay, hyperactivity, growth retardation with growth hormone deficiency, insulin-dependent diabetes, and mild facial dysmorphism. Most of these features have been previously described in individuals with simple terminal deletion of 2q37. Pure duplications of the proximal chromosome 2q are rare and no specific syndrome has been defined yet, so the contribution of the 2q14.1q14.2 duplication to the phenotype of the patient is unknown. These findings underscore the need to explore apparently balanced chromosomal rearrangements inherited from a phenotypically normal parent in subjects with autism and/or developmental delay. In addition, they provide further evidence indicating that chromosome 2q terminal deletions are among the most frequently reported cytogenetic abnormalities in individuals with autism. PMID:20684015

Devillard, Françoise; Guinchat, Vincent; Moreno-De-Luca, Daniel; Tabet, Anne-Claude; Gruchy, Nicolas; Guillem, Pascale; Nguyen Morel, Marie-Ange; Leporrier, Nathalie; Leboyer, Marion; Jouk, Pierre-Simon; Lespinasse, James; Betancur, Catalina

2010-09-01

291

Myelodysplastic syndrome with 5q deletion following IgM monoclonal gammopathy, showing gene mutation MYD88 L265P.  

PubMed

Patients affected by monoclonal gammopathy of undetermined significance (MGUS) very rarely develop a myelodysplastic syndrome (MDS). However, it was also demonstrated that MGUS patients had a significantly increased risk of developing MDS compared to the general population. We report a case of 5q-syndrome following a MGUS IgMk with mutation of MYD88 L256P. To our knowledge, this is the first case of del(5q) MDS following MGUS IgMk with the MYD88 L256P mutation in which there is coexistence of the markers of the two clonal diseases, but as an expression of distinct pathological features. PMID:25159121

Zagaria, Antonella; Coccaro, Nicoletta; Tota, Giuseppina; Anelli, Luisa; Minervini, Angela; Casieri, Paola; Cellamare, Angelo; Minervini, Crescenzio Francesco; Brunetti, Claudia; Ricco, Alessandra; Orsini, Paola; Cumbo, Cosimo; Specchia, Giorgina; Albano, Francesco

2015-01-01

292

Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.  

PubMed

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability. PMID:23033313

Bisschoff, Izak J; Zeschnigk, Christine; Horn, Denise; Wellek, Brigitte; Rieß, Angelika; Wessels, Maja; Willems, Patrick; Jensen, Peter; Busche, Andreas; Bekkebraten, Jens; Chopra, Maya; Hove, Hanne Dahlgaard; Evers, Christina; Heimdal, Ketil; Kaiser, Ann-Sophie; Kunstmann, Erdmut; Robinson, Kristina Lagerstedt; Linné, Maja; Martin, Patricia; McGrath, James; Pradel, Winnie; Prescott, Katrina E; Roesler, Bernd; Rudolf, Gorazd; Siebers-Renelt, Ulrike; Tyshchenko, Nataliya; Wieczorek, Dagmar; Wolff, Gerhard; Dobyns, William B; Morris-Rosendahl, Deborah J

2013-01-01

293

Study of two patients with craniosynostosis and deletions of 11q: One with features of Saethre-Chotzen syndrome and the other with concomitant partial trisomy 4q  

SciTech Connect

Partial monosomy 11q is associated with metopic craniosynostosis and trigonocephaly. Prominant features in the over 30 reported cases include downslanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, wide/depressed nasal bridge, low set malformed ears, downturned mouth, micro/retrognathia, digital and cardiac anomalies and psychomotor retardation. We evaluated two patients referred for abnormal head shape. The first carried a diagnosis of Saethre-Chotzen syndrome due to brachycephaly, facial asymmetry, ptosis, cupped ears, sundactyly of 2nd and 3rd digits, developmental delay, and VSD. Karyotype revealed 46,XY,del(11)(q24.1{yields}qter). No abnormality was noted of chromosome 7p, where the Saethre-Chotzen syndrome locus has been mapped. This suggests genetic heterogeneity for this condition. The second patient had no prior diagnosis. He had trigonocephaly, bilateral cryptorchidism and inguinal hernias. He also had hypotelorism, epicanthal folds, synophrys, posteriorly rotated ears, horizontal crease below his lower lip, unilateral single palmar crease, mild soft tissue syndactyly and a shawl scrotum. His karyotype of 46,XY,-11,+der(11)t(4;11)(q31.3;q25) revealed both partial 11q monosomy and partial 4q trisomy (the latter associated with cryptorchidism, horizontal chin crease and single palmar crease). Deletions of 11q appear to produce a wide spectrum of defects, which may even mimic other known craniosynostotic conditions. Study of these patients may lead to the identification of new genes involved in craniofacial morphogenesis.

Morsey, S. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)]|[Kennedy-Krieger Institute, Baltimore, MD (United States); Lewanda, A.F. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)]|[Children`s National Medical Center, Washington, DC (United States); Reid, C.S. [Cooper Hospitsl/Univ. Medical Center, Camden, NJ (United States)

1994-09-01

294

Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion.  

PubMed

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two neurodevelopmental disorders most often caused by deletions of the same region of paternally inherited and maternally inherited human chromosome 15q, respectively. AS is a single gene disorder, caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, while PWS is still considered a contiguous gene disorder. Rare individuals with PWS who carry atypical microdeletions on chromosome 15q have narrowed the critical region for this disorder to a 108 kb region that includes the SNORD116 snoRNA cluster and the Imprinted in Prader-Willi (IPW) non-coding RNA. Here we report the derivation of induced pluripotent stem cells (iPSCs) from a PWS patient with an atypical microdeletion that spans the PWS critical region. We show that these iPSCs express brain-specific portions of the transcripts driven by the PWS imprinting center, including the UBE3A antisense transcript (UBE3A-ATS). Furthermore, UBE3A expression is imprinted in most of these iPSCs. These data suggest that UBE3A imprinting in neurons only requires UBE3A-ATS expression, and no other neuron-specific factors. These data also suggest that a boundary element lying within the PWS critical region prevents UBE3A-ATS expression in non-neural tissues. PMID:24363065

Martins-Taylor, Kristen; Hsiao, Jack S; Chen, Pin-Fang; Glatt-Deeley, Heather; De Smith, Adam J; Blakemore, Alexandra I F; Lalande, Marc; Chamberlain, Stormy J

2014-05-01

295

Amelioration of the typical cognitive phenotype in a patient with the 5pter deletion associated with Cri-du-chat syndrome in addition to a partial duplication of CTNND2.  

PubMed

Cri-du-chat is a rare congenital syndrome characterized by intellectual disability, severe speech/developmental delay, dysmorphic features, and additional syndromic findings. The etiology of this disorder is well known, and is attributed to a large deletion on chromosome 5 that typically ranges from band 5p15.2 to the short arm terminus. This region contains CTNND2, a gene encoding a neuronal-specific protein, delta-catenin, which plays a critical role in cellular motility and brain function. The exact involvement of CTNND2 in the cognitive functionality of individuals with Cri-du-chat has not been fully deciphered, but it is thought to be significant. This report describes an 8-year-old African-American female with a complex chromosome 5 abnormality and a relatively mild case of cri-du-chat syndrome. Because of the surprisingly mild cognitive phenotype, although a karyotype had confirmed the 5p deletion at birth, an oligo-SNP microarray was obtained to further characterize her deletion. The array revealed a complex rearrangement, including a breakpoint in the middle of CTNND2, which resulted in a partial deletion and partial duplication of that gene. The array also verified the expected 5p terminal deletion. Although the patient has a significant deletion in CTNND2, half of the gene (including the promoter region) is not only preserved, but is duplicated. The patient's milder cognitive and behavioral presentation, in conjunction with her atypical 5p alteration, provides additional evidence for the role of CTNND2 in the cognitive phenotype of individuals with Cri-du-chat. PMID:24677774

Sardina, Jennifer M; Walters, Allyson R; Singh, Kathryn E; Owen, Renius X; Kimonis, Virginia E

2014-07-01

296

The Subtelomeric khipu Satellite Repeat from Phaseolus vulgaris: Lessons Learned from the Genome Analysis of the Andean Genotype G19833  

PubMed Central

Subtelomeric regions in eukaryotic organisms are known for harboring species-specific tandemly repeated satellite sequences. However, studies on the molecular organization and evolution of subtelomeric repeats are scarce, especially in plants. Khipu is a satellite DNA of 528-bp repeat unit, specific of the Phaseolus genus, with a subtelomeric distribution in common bean, P. vulgaris. To investigate the genomic organization and the evolution of khipu, we performed genome-wide analysis on the complete genome sequence of the common bean genotype G19833. We identified 2,460 khipu units located at most distal ends of the sequenced regions. Khipu units are arranged in discrete blocks of 2–55 copies and are heterogeneously distributed among the different chromosome ends of G19833 (from 0 to 555 khipus units per chromosome arm). Phylogenetically related khipu units are spread between numerous chromosome ends, suggesting frequent exchanges between non-homologous subtelomeres. However, most subclades contain numerous khipu units from only one or few chromosome ends indicating that local duplication is also driving khipu expansion. Unexpectedly, we also identified 81 khipu units located at centromeres. All the centromeric khipu units belong to a single divergent clade also comprised of a few units from several subtelomeres, suggesting that a few sequence exchanges between centromeres and subtelomeres took place in the common bean genome. The divergence and low copy number of these centromeric units from the subtelomeric units could explain why they were not detected by FISH (Fluorescence in situ Hybridization) although it can not be excluded that these centromeric units may have resulted from errors in the pseudomolecule assembly. Altogether our data highlight extensive sequence exchanges in subtelomeres between non-homologous chromosomes in common bean and confirm that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes. PMID:24137164

Richard, Manon M. S.; Chen, Nicolas W. G.; Thareau, Vincent; Pflieger, Stéphanie; Blanchet, Sophie; Pedrosa-Harand, Andrea; Iwata, Aiko; Chavarro, Carolina; Jackson, Scott A.; Geffroy, Valérie

2013-01-01

297

Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course.  

PubMed

Kleefstra syndrome (KS), previously known as the 9q subtelomeric deletion syndrome (9qSTDS) is caused by haploinsufficiency of the EHMT1 gene. Both a single mutation and 9q34 microdeletions encompassing the entire gene can be responsible for this syndrome which is characterized by intellectual disability, hypotonia, and typical dysmorphisms, and may be associated with congenital heart and/or renal defects and epilepsy. Its behavioral phenotype has recently been described and comprises particular sleep disturbances and apathy. In this report, the evolution of the behavioral profile of KS is outlined by the description of three female patients aged 19, 33, and 43 years, respectively. In two patients, the syndrome was caused by an intragenic mutation and in the third by a 9q34 microdeletion encompassing the EHMT1 gene. MRI scanning of the brain in the two eldest patients demonstrated multifocal subcortical signal abnormalities. In general, the severity of the behavioral and motor deficiencies increased over time and became apparent after adolescence. It is concluded that the "regressive" phenotype of KS seems to be associated with the EHMT1 gene in particular. In addition, the utility of uncritical use of a classificatory diagnostic approach is discussed in the context of the motor and motivational disturbances that are prominent in this syndrome. PMID:21910222

Verhoeven, Willem M A; Egger, Jos I M; Vermeulen, Karlijn; van de Warrenburg, Bart P C; Kleefstra, Tjitske

2011-10-01

298

Deletion (2)(q37)  

SciTech Connect

We report on a 5-month-old girl with widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Initial clinical assessment suggested the diagnosis of Ullrich-Turner syndrome. Chromosome analysis showed a 46,XX,del(2)(q37) karyotype in peripheral lymphocytes. We compare her findings to those of other reported patients with terminal deletions of 2q. 8 refs., 2 figs., 1 tab.

Stratton, R.F.; Tolworthy, J.A.; Young, R.S. [South Texas Genetics Center, San Antonio, TX (United States)

1994-06-01

299

Computerized Neurocognitive Profile in Young People with 22q11.2 Deletion Syndrome Compared to Youths with Schizophrenia and At-risk for Psychosis  

PubMed Central

Objective Adults with 22q11.2 Deletion Syndrome (22q11DS) have increased prevalence of schizophrenia features. Our goal is to compare the neurocognitive profile in 22q11DS, schizophrenia and individuals at risk for schizophrenia. Methods Twenty-one 22q11DS patients (8y-32y, mean 14.9y, 15M 6F) were matched to four comparison groups on age: low risk (n=21), first-degree family members of schizophrenia patients (genetic risk, n=20), individuals exhibiting putatively prodromal symptoms (clinical risk, n=19), and patients with schizophrenia (n=21). All participants received semi-structured interviews [Diagnostic Interview for Genetic Studies (DIGS) and the Structured Interview for Prodromal Syndromes (SIPS)], and a computerized neurocognitive battery (CNB) measuring the following domains: Abstraction and Mental Flexibility, Attention, Working Memory, Verbal Memory, Face Memory, Spatial Memory, Language, Spatial Processing, Sensorimotor Dexterity, and Emotion Processing. Results 60% of 22q11DS participants met SIPS criteria for prodromal symptoms and one participant met criteria for paranoid schizophrenia. 38% met criteria for Depressive Disorders. All 22q11DS participants successfully completed the CNB. 22q11DS participants were significantly less accurate in nearly all domains, but had similar speed of response compared to the other groups. Their profile resembled that of the psychosis groups in accuracy and speed, except for more pronounced deficits in accuracy for face memory and emotion processing. Conclusion Subthreshold psychotic symptoms are present in a high proportion of 22q11DS participants. Deficits shown in the CNB are more pronounced for accuracy than speed relative to the psychosis groups with similar profiles. Similar deficits have been described in the 22q11DS population using non-computerized measures, which require increased testing time. PMID:22170773

Goldenberg, Paula C.; Calkins, Monica E.; Richard, Jan; McDonald-McGinn, Donna; Zackai, Elaine; Mitra, Nandita; Emanuel, Beverly; Devoto, Marcella; Borgmann-Winter, Karin; Kohler, Christian; Conroy, Catherine G.; Gur, Ruben; Gur, Raquel

2012-01-01

300

The effect of hypocalcemia in early childhood on autism-related social and communication skills in patients with 22q11 deletion syndrome.  

PubMed

22q11 deletion syndrome (22qDS), also known as DiGeorge syndrome, is a copy number variant disorder that has a diverse clinical presentation including hypocalcaemia, learning disabilities, and psychiatric disorders. Many patients with 22q11DS present with signs that overlap with autism spectrum disorder (ASD) yet the possible physiological mechanisms that link 22q11DS with ASD are unknown. We hypothesized that early childhood hypocalcemia influences the neurobehavioral phenotype of 22q11DS. Drawing on a longitudinal cohort of 22q11DS patients, we abstracted albumin-adjusted serum calcium levels from 151 participants ranging in age from newborn to 19.5 years (mean 2.5 years). We then examined a subset of 20 infants and toddlers from this group for the association between the lowest calcium level on record and scores on the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC). The mean (SD) age at calcium testing was 6.2 (8.5) months, whereas the mean (SD) age at the CSBS-DP ITC assessment was 14.7 (3.8) months. Lower calcium was associated with significantly greater impairment in the CSBS-DP ITC Social (p < 0.05), Speech (p < 0.01), and Symbolic domains (p < 0.05), in regression models adjusted for sex, age at blood draw, and age at the psychological assessment. Nevertheless, these findings are limited by the small sample size of children with combined data on calcium and CSBS-DP ITC, and hence will require replication in a larger cohort with longitudinal assessments. Considering the role of calcium regulation in neurodevelopment and neuroplasticity, low calcium during early brain development could be a risk factor for adverse neurobehavioral outcomes. PMID:25267002

Muldoon, Meghan; Ousley, Opal Y; Kobrynski, Lisa J; Patel, Sheena; Oster, Matthew E; Fernandez-Carriba, Samuel; Cubells, Joseph F; Coleman, Karlene; Pearce, Bradley D

2014-09-30

301

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report  

PubMed Central

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common childhood genetic disorder and is characterized by an elevated risk for immune disorders, as 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1?, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r = 0.851, p = 0.004; r = 0.580, p = 0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r = 0.795, p = 0.033; r = 0.774, p = 0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive relationship between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry. PMID:23353117

Ross, Heather; Guo, Ying; Coleman, Karlene; Ousley, Opal; Miller, Andrew

2013-01-01

302

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report.  

PubMed

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1?, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r=0.851, p=0.004; r=0.580, p=0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r=0.795, p=0.033; r=0.774, p=0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry. PMID:23353117

Ross, Heather E; Guo, Ying; Coleman, Karlene; Ousley, Opal; Miller, Andrew H

2013-07-01

303

Expanding the spectrum of microdeletion 4q21 syndrome: a partial phenotype with incomplete deletion of the minimal critical region and a new association with cleft palate and Pierre Robin sequence.  

PubMed

Microdeletion 4q21 syndrome has been described in about a dozen patients with deletions ranging from 3.2 to 15.1 MB with similar features including the distinctive facial characteristics of broad forehead, hypertelorism, and prominent front teeth, with severe growth delay, developmental delay, and neonatal hypotonia. A 1.37 MB minimal critical region has been described that accounts for this shared phenotype and includes five known genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1. We report on two new patients found through single nucleotide polymorphism (SNP) microarray testing that expand the reported phenotype. Patient 1 has a novel deletion of 2.0 MB, the smallest reported deletion, which involves only a partial deletion of the minimal critical region, including the genes HNRNPD, HNRPDL, and ENOPH1. She shares much of the typical phenotype including moderate developmental delay, unusual facial features, small hands and feet, but not any growth delay or neonatal hypotonia. This patient allows further genotype-phenotype correlation of the genes in the minimal critical region, and supports that heterozygous loss of PRKG2 leads to the growth delay. Patient 2 has a novel 3.4 MB deletion that includes the entire critical region, and has typical features, but also presented with cleft palate and Pierre Robin sequence, which have not been previously described. A gene reported to be associated with inherited cleft palate, SCD5, is in the deleted region in this patient, which suggests it may be playing a role in palate formation. Taken together, these patients allow for an expansion of the microdeletion 4q21 syndrome and provide candidate genes for particular features of the phenotype. PMID:23913759

Bhoj, Elizabeth; Halbach, Sara; McDonald-McGinn, Donna; Tan, Christopher; Lande, Rachel; Waggoner, Darrel; Zackai, Elaine

2013-09-01

304

Identification of Four Highly Conserved Genes between Breakpoint Hotspots BP1 and BP2 of the Prader-Willi\\/Angelman Syndromes Deletion Region That Have Undergone Evolutionary Transposition Mediated by Flanking Duplicons  

Microsoft Academic Search

Prader-Willi and Angelman syndromes (PWS and AS) typically result from an ?4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3). HERC2 and other duplicons map to these BP regions, with the 2-Mb PWS\\/AS imprinted domain just distal of BP2. Previously, the presence of genes and

J. H. Chai; D. P. Locke; J. M. Greally; J. H. M. Knoll; T. Ohta; J. Dunai; A. Yavor; E. E. Eichler; R. D. Nicholls

2003-01-01

305

Molecular characterization of two deletion events involving Alu -sequences, one novel base substitution and two tentative hotspot mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene in five patients with Lesch-Nyhan syndrome  

Microsoft Academic Search

Mutations identified in the hypoxanthine phosphoribosyltransferase (HPRT) gene of patients with Lesch-Nyhan (LN) syndrome\\u000a are dominated by simple base substitutions. Few hotspot positions have been identified, and only three large genomic rearrangements\\u000a have been characterized at the molecular level. We have identified one novel mutation, two tentative hot spot mutations, and\\u000a two deletions by direct sequencing of HPRT cDNA or

T. Tvrdik; Suzanne Marcus; Sai-Mei Hou; Susann Fält; Peri Noori; Natalia Podlutskaja; Folker Hanefeld; Petter Strømme; Bo Lambert

1998-01-01

306

Is monosomy 5 an uncommon aberration? Fluorescence in situ hybridization reveals translocations and deletions in myelodysplastic syndromes or acute myelocytic leukemia.  

PubMed

Acquired loss of material from chromosome 5 in bone marrow cells is common in myelodysplastic syndromes (MDS) and acute myelocytic leukemia (AML). In this study, we have applied fluorescence in situ hybridization (FISH) analyses with probes for the three regions 5p15.2, 5q31, 5q33-q34, and whole chromosome 5 painting probes (WCP 5) to investigate what further information could be gained regarding the cytogenetic abnormalities of chromosome 5 in 35 patients with MDS or AML. With FISH, a del(5q) was found in all patients except for two. Translocations of material from chromosome 5 were found in 10 patients. Among 16 patients with clones of monosomy 5 seen by cytogenetics, 14 had deletions or translocations. Different breakpoints on chromosome 5 were observed. In conclusion, the extended FISH analyses yielded additional information about chromosome 5 abnormalities in 60% of the patients. Of interest is the finding of a high proportion of translocations and that monosomy 5 occurs less often than is generally believed. PMID:12699885

Bram, Susanne; Swolin, Birgitta; Rödjer, Stig; Stockelberg, Dick; Ogärd, Inger; Bäck, Hans

2003-04-15

307

Candidate gene analysis using genomic quantitative PCR: identification of ADAMTS13 large deletions in two patients with Upshaw-Schulman syndrome  

PubMed Central

Direct sequencing is a popular method to discover mutations in candidate genes responsible for hereditary diseases. A certain type of mutation, however, can be missed by the method. Here, we report a comprehensive genomic quantitative polymerase chain reaction (qPCR) to complement the weakness of direct sequencing. Upshaw-Schulman syndrome (USS) is a recessively inherited disease associated with severe deficiency of plasma ADAMTS13 activity. We previously analyzed ADAMTS13 in 47 USS patients using direct sequencing, and 44 of them had either homozygous or compound heterozygous mutations. Then, we sought to reveal more extensive defects of ADAMTS13 in the remaining three patients. We quantified copy numbers of each ADAMTS13 exon in the patients by using genomic qPCR. Each primer pair was designed to contain at least one of the two primers used in direct sequencing, to avoid missing any exonic deletions. The qPCR demonstrated heterozygous loss of exons 7 and 8 in one patient and exon 27 in the other, and further analysis revealed c.746_987+373del1782 and c.3751_3892+587del729, respectively. Genomic qPCR provides an effective method for identifying extensive defects of the target genes. PMID:24936513

Eura, Yuka; Kokame, Koichi; Takafuta, Toshiro; Tanaka, Ryojiro; Kobayashi, Hikaru; Ishida, Fumihiro; Hisanaga, Shuichi; Matsumoto, Masanori; Fujimura, Yoshihiro; Miyata, Toshiyuki

2014-01-01

308

Redundant roles for histone H3 N-terminal lysine residues in subtelomeric gene repression in Saccharomyces cerevisiae.  

PubMed Central

The transcription of genes located in subtelomeric regions of yeast chromosomes is repressed relative to the rest of the genome. This repression requires wild-type nucleosome levels but not the telomere silencing factors Sir2, Sir3, Sir4, and Rap1. Subtelomeric heterochromatin is characterized by the absence of acetylation or methylation of histone H3 lysine residues, but it is not known whether histone H3 hypoacetylation or hypomethylation is a prerequisite for the establishment of subtelomeric heterochromatin. We have systematically mutated the N-terminal tails of histone H3 and H4 in Saccharomyces cerevisiae and characterized the effects each mutant has on genome-wide expression. Our results show that subtelomeric transcriptional repression is dependent on the histone H3 N-terminal domain, but not the histone H4 N-terminal domain. Mutating lysine-4, lysine-9, lysine-14, lysine-18, lysine-23, and lysine-27 to glycine in histone H3 is also sufficient to significantly reduce subtelomeric gene repression. Individual histone H3 lysine mutations, however, have little effect on subtelomeric gene repression or genome-wide expression, indicating that these six lysine residues have redundant functions. We propose that acetylation and methylation of histone H3 N-terminal lysine residues act as redundant mechanisms to demarcate regions of euchromatin from heterochromatin. PMID:15280228

Martin, Amy M; Pouchnik, Derek J; Walker, Jennifer L; Wyrick, John J

2004-01-01

309

Simultaneous Copy Number Losses within Multiple Subtelomeric Regions in Early-Onset Type2 Diabetes Mellitus  

PubMed Central

Genetic factors play very important roles in the onset and progression of type 2 diabetes mellitus (T2DM). However, the genetic factors correlating with T2DM onset have not as yet been fully clarified. We previously found that copy number losses in the subtelomeric region on chromosome 4p16.3 were detected in early-onset Japanese T2DM patients (onset age <35 years) at a high frequency. Herein, we additionally found two novel copy number losses within the subtelomeric regions on chromosomes 16q24.2-3 and 22q13.31-33, which have significant associations with early-onset Japanese T2DM. The associations were statistically significant by Fisher's exact tests with P values of 5.19×10?3 and 1.81×10?3 and odds ratios of 5.7 and 4.4 for 16q24.2-3 and 22q13.31-33, respectively. Furthermore, copy number variation (CNV) analysis of the whole genome using the CNV BeadChip system verified simultaneous copy number losses in all three subtelomeric regions in 11 of our 100 T2DM subjects, while none of 100 non-diabetic controls showed the copy number losses in all three regions. Our results suggest that the mechanism underlying induction of CNVs is involved in the pathogenesis of early-onset T2DM. Thus, copy number losses within multiple subtelomeric regions are strongly associated with early-onset T2DM and examination of simultaneous CNVs in these three regions may lead to the development of an accurate and selective procedure for detecting genetic susceptibility to T2DM. PMID:24709989

Kodama, Shinjiro; Yamada, Tetsuya; Imai, Junta; Sawada, Shojiro; Takahashi, Kei; Tsukita, Sohei; Kaneko, Keizo; Uno, Kenji; Ishigaki, Yasushi; Oka, Yoshitomo; Katagiri, Hideki

2014-01-01

310

In Search of the Optimal Surgical Treatment for Velopharyngeal Dysfunction in 22q11.2 Deletion Syndrome: A Systematic Review  

PubMed Central

Background Patients with the 22q11.2 deletion syndrome (22qDS) and velopharyngeal dysfunction (VPD) tend to have residual VPD following surgery. This systematic review seeks to determine whether a particular surgical procedure results in superior speech outcome or less morbidity. Methodology/ Principal Findings A combined computerized and hand-search yielded 70 studies, of which 27 were deemed relevant for this review, reporting on a total of 525 patients with 22qDS and VPD undergoing surgery for VPD. All studies were levels 2c or 4 evidence. The methodological quality of these studies was assessed using criteria based on the Cochrane Collaboration's tool for assessing risk of bias. Heterogeneous groups of patients were reported on in the studies. The surgical procedure was often tailored to findings on preoperative imaging. Overall, 50% of patients attained normal resonance, 48% attained normal nasal emissions scores, and 83% had understandable speech postoperatively. However, 5% became hyponasal, 1% had obstructive sleep apnea (OSA), and 17% required further surgery. There were no significant differences in speech outcome between patients who underwent a fat injection, Furlow or intravelar veloplasty, pharyngeal flap pharyngoplasty, Honig pharyngoplasty, or sphincter pharyngoplasty or Hynes procedures. There was a trend that a lower percentage of patients attained normal resonance after a fat injection or palatoplasty than after the more obstructive pharyngoplasties (11–18% versus 44–62%, p?=?0.08). Only patients who underwent pharyngeal flaps or sphincter pharyngoplasties incurred OSA, yet this was not statistically significantly more often than after other procedures (p?=?0.25). More patients who underwent a palatoplasty needed further surgery than those who underwent a pharyngoplasty (50% versus 7–13%, p?=?0.03). Conclusions/ Significance In the heterogeneous group of patients with 22qDS and VPD, a grade C recommendation can be made to minimize the morbidity of further surgery by choosing to perform a pharyngoplasty directly instead of only a palatoplasty. PMID:22470558

Spruijt, Nicole E.; ReijmanHinze, Judith; Hens, Greet; Vander Poorten, Vincent; Mink van der Molen, Aebele B.

2012-01-01

311

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome.  

PubMed

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ?15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact that exenatide did not reduce ghrelin levels in fed mice and food intake of ghrelin(-/-) mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexic effect in PWS individuals. PMID:24735326

Lin, Dahe; Wang, Qi; Ran, Haiying; Liu, Kai; Wang, Yao; Wang, Juanjuan; Liu, Yazhen; Chen, Ruichuan; Sun, Yuxiang; Liu, Runzhong; Ding, Feng

2014-07-01

312

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader–Willi syndrome: A comparison between maternal uniparental disomy and deletion cases  

PubMed Central

This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader–Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P?=?0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P?=?0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P?=?0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P?=?0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID:24850752

Ogata, Hiroyuki; Ihara, Hiroshi; Murakami, Nobuyuki; Gito, Masao; Kido, Yasuhiro; Nagai, Toshiro

2014-01-01

313

Terminal 14q32.33 deletion: genotype-phenotype correlation.  

PubMed

We report on a female infant presenting with psychomotor retardation and facial dysmorphism. Cytogenetic studies showed an abnormal chromosome 14 with ectopic NOR sequences at the extremity of the long arm with a terminal 14q32.33 deletion. Review of the eight cases with pure terminal 14q32.3 deletions described to date documented that our observation is the smallest terminal 14q deletion ever reported. Thus, genotype-phenotype correlation allows us to delimit the critical region for mental retardation, hypotonia, epi-telecanthus, short bulbous nose, long philtrum, thin upper lip, and small mouth observed in 14 qter deletions to the subtelomeric 1.6 Mb of chromosome 14. PMID:17022077

Maurin, M-L; Brisset, S; Le Lorc'h, M; Poncet, V; Trioche, P; Aboura, A; Labrune, P; Tachdjian, G

2006-11-01

314

Locus-specific control of DNA resection and suppression of subtelomeric VSG recombination by HAT3 in the African trypanosome.  

PubMed

The African trypanosome, Trypanosoma brucei, is a parasitic protozoan that achieves antigenic variation through DNA-repair processes involving Variant Surface Glycoprotein (VSG) gene rearrangements at subtelomeres. Subtelomeric suppression of DNA repair operates in eukaryotes but little is known about these controls in trypanosomes. Here, we identify a trypanosome histone acetyltransferase (HAT3) and a deacetylase (SIR2rp1) required for efficient RAD51-dependent homologous recombination. HAT3 and SIR2rp1 were required for RAD51-focus assembly and disassembly, respectively, at a chromosome-internal locus and a synthetic defect indicated distinct contributions to DNA repair. Although HAT3 promoted chromosome-internal recombination, it suppressed subtelomeric VSG recombination, and these locus-specific effects were mediated through differential production of ssDNA by DNA resection; HAT3 promoted chromosome-internal resection but suppressed subtelomeric resection. Consistent with the resection defect, HAT3 was specifically required for the G2-checkpoint response at a chromosome-internal locus. HAT3 also promoted resection at a second chromosome-internal locus comprising tandem-duplicated genes. We conclude that HAT3 and SIR2rp1 can facilitate temporally distinct steps in DNA repair. HAT3 promotes ssDNA formation and recombination at chromosome-internal sites but has the opposite effect at a subtelomeric VSG. These locus-specific controls reveal compartmentalization of the T. brucei genome in terms of the DNA-damage response and suppression of antigenic variation by HAT3. PMID:25300492

Glover, Lucy; Horn, David

2014-11-10

315

Locus-specific control of DNA resection and suppression of subtelomeric VSG recombination by HAT3 in the African trypanosome  

PubMed Central

The African trypanosome, Trypanosoma brucei, is a parasitic protozoan that achieves antigenic variation through DNA-repair processes involving Variant Surface Glycoprotein (VSG) gene rearrangements at subtelomeres. Subtelomeric suppression of DNA repair operates in eukaryotes but little is known about these controls in trypanosomes. Here, we identify a trypanosome histone acetyltransferase (HAT3) and a deacetylase (SIR2rp1) required for efficient RAD51-dependent homologous recombination. HAT3 and SIR2rp1 were required for RAD51-focus assembly and disassembly, respectively, at a chromosome-internal locus and a synthetic defect indicated distinct contributions to DNA repair. Although HAT3 promoted chromosome-internal recombination, it suppressed subtelomeric VSG recombination, and these locus-specific effects were mediated through differential production of ssDNA by DNA resection; HAT3 promoted chromosome-internal resection but suppressed subtelomeric resection. Consistent with the resection defect, HAT3 was specifically required for the G2-checkpoint response at a chromosome-internal locus. HAT3 also promoted resection at a second chromosome-internal locus comprising tandem-duplicated genes. We conclude that HAT3 and SIR2rp1 can facilitate temporally distinct steps in DNA repair. HAT3 promotes ssDNA formation and recombination at chromosome-internal sites but has the opposite effect at a subtelomeric VSG. These locus-specific controls reveal compartmentalization of the T. brucei genome in terms of the DNA-damage response and suppression of antigenic variation by HAT3. PMID:25300492

Glover, Lucy; Horn, David

2014-01-01

316

Sex chromosome differentiation in Humulus japonicus Siebold & Zuccarini, 1846 (Cannabaceae) revealed by fluorescence in situ hybridization of subtelomeric repeat  

PubMed Central

Abstract Humulus japonicus Siebold et Zucc (Japanese hop) is a dioecious species of the family Cannabaceae. The chromosome number is 2n = 16 = 14 + XX for females and 2n = 17 = 14 + XY1Y2 for male. To date, no fluorescence in situ hybridization (FISH) markers have been established for the identification of Humulus japonicus sex chromosomes. In this paper, we report a method for the mitotic and meiotic sex chromosome differentiation in Humulus japonicus by FISH for HJSR, a high copy subtelomeric repeat. The signal is present in the subtelomeric region of one arm of the X chromosome. We demonstrate that males have two Y chromosomes that differ in FISH signal with the HJSR probe. Indeed, the HJSR probe hybridizes to a subtelomeric region on both arms of chromosome Y1 but not of chromosome Y2. The orientation and position of pseudoautosomal regions (PAR1 and PAR2) were also determined. PMID:24260665

Alexandrov, Oleg S.; Divashuk, Mikhail G.; Yakovin, Nikolay A.; Karlov, Gennady I.

2012-01-01

317

Isolation and sequence analysis of the wheat B genome subtelomeric DNA  

PubMed Central

Background Telomeric and subtelomeric regions are essential for genome stability and regular chromosome replication. In this work, we have characterized the wheat BAC (bacterial artificial chromosome) clones containing Spelt1 and Spelt52 sequences, which belong to the subtelomeric repeats of the B/G genomes of wheats and Aegilops species from the section Sitopsis. Results The BAC library from Triticum aestivum cv. Renan was screened using Spelt1 and Spelt52 as probes. Nine positive clones were isolated; of them, clone 2050O8 was localized mainly to the distal parts of wheat chromosomes by in situ hybridization. The distribution of the other clones indicated the presence of different types of repetitive sequences in BACs. Use of different approaches allowed us to prove that seven of the nine isolated clones belonged to the subtelomeric chromosomal regions. Clone 2050O8 was sequenced and its sequence of 119 737 bp was annotated. It is composed of 33% transposable elements (TEs), 8.2% Spelt52 (namely, the subfamily Spelt52.2) and five non-TE-related genes. DNA transposons are predominant, making up 24.6% of the entire BAC clone, whereas retroelements account for 8.4% of the clone length. The full-length CACTA transposon Caspar covers 11 666 bp, encoding a transposase and CTG-2 proteins, and this transposon accounts for 40% of the DNA transposons. The in situ hybridization data for 2050O8 derived subclones in combination with the BLAST search against wheat mapped ESTs (expressed sequence tags) suggest that clone 2050O8 is located in the terminal bin 4BL-10 (0.95-1.0). Additionally, four of the predicted 2050O8 genes showed significant homology to four putative orthologous rice genes in the distal part of rice chromosome 3S and confirm the synteny to wheat 4BL. Conclusion Satellite DNA sequences from the subtelomeric regions of diploid wheat progenitor can be used for selecting the BAC clones from the corresponding regions of hexaploid wheat chromosomes. It has been demonstrated for the first time that Spelt52 sequences were involved in the evolution of terminal regions of common wheat chromosomes. Our research provides new insights into the microcollinearity in the terminal regions of wheat chromosomes 4BL and rice chromosome 3S. PMID:19732459

Salina, Elena A; Sergeeva, Ekaterina M; Adonina, Irina G; Shcherban, Andrey B; Afonnikov, Dmitry A; Belcram, Harry; Huneau, Cecile; Chalhoub, Boulos

2009-01-01

318

S5: Potential for cross-hybridization among sub-telomeric probes The sequences of inter-genic probes used in the ChIp-chip experiments were downloaded from  

E-print Network

S5: Potential for cross-hybridization among sub-telomeric probes The sequences of inter search (blastclust algorithm) to identify sub-telomeric probes with high sequence similarity. The plots below show the number of sub-telomeric probes that have a sequence identity of 70% (A), 75% (B) and 80

Babu, M. Madan

319

Both subtelomeric regions are required and sufficient for specific DNA fragmentation during macronuclear development in Stylonychia lemnae  

PubMed Central

Background: Programmed DNA-reorganization and DNA-elimination events take place frequently during cellular differentiation. An extreme form of such processes, involving DNA reorganization, DNA elimination and DNA fragmentation, is found during macronuclear differentiation in hypotrichous ciliates. Ciliated protozoa can therefore serve as a model system to analyze the molecular basis of these processes during cellular differentiation in eukaryotic cells. Results: Using a biological approach to identify cis-acting sequences involved in DNA fragmentation, we show that in the hypotrichous ciliate Stylonychia lemnae sequences required for specific DNA processing are localized in the 3'- and the 5'-subtelomeric regions of the macronuclear precursor sequence. They can be present at various positions in the two subtelomeric regions, and an interaction between the two regions seems to occur. Sequence comparison revealed a consensus inverted repeat in both subtelomeric regions that is almost identical to the putative Euplotes chromosome breakage sequence (E-Cbs), also identified by sequence comparison. When this sequence was mutagenized, a processed product could no longer be detected, demonstrating that the sequence plays a crucial role in DNA processing. By injecting a construct into the developing macronucleus, which exclusively contains the subtelomeric regions of the Stylonychia ?l-tubulin gene, we show that subtelomeric regions are not only required but are also sufficient for DNA processing in Stylonychia. Conclusions: Our results indicate that an inverted repeat with the core sequence 5'-TGAA present in both subtelomeric regions acts as a Cbs in Stylonychia. The results allow us to propose a mechanistic model for DNA processing in this ciliate. PMID:11182888

Jönsson, Franziska; Steinbrück, Günther; Lipps, Hans J

2001-01-01

320

The yeast Cyc8–Tup1 complex cooperates with Hda1p and Rpd3p histone deacetylases to robustly repress transcription of the subtelomeric FLO1 gene  

PubMed Central

We demonstrate that the yeast flocculation gene, FLO1, is representative of a distinct subset of subtelomeric genes that are robustly repressed by the Cyc8–Tup1 complex. We have examined Cyc8–Tup1 localisation, histone acetylation and long-range chromatin remodelling within the extensive FLO1 upstream region. We show that Cyc8–Tup1 is localised in a DNase I hypersensitive site within an ordered array of strongly positioned nucleosomes around ? 700 base pairs upstream of the transcription start site. In cyc8 deletion mutant strains, Tup1p localisation is absent, with concomitant histone hyperacetylation of adjacent regions at the FLO1 promoter. This is accompanied by extensive histone depletion across the upstream region and gene activation. The yeast histone deacetylases, Hda1p and Rpd3p, occupy the repressed FLO1 promoter region in a Cyc8–Tup1 dependent manner and coordinate histone deacetylation, nucleosome stabilisation and gene repression. Moreover, we show that the ATP-dependent chromatin remodelling complex Swi–Snf occupies the site vacated by Cyc8–Tup1 in a cyc8 mutant. These data suggest that distinctly bound Cyc8–Tup1 cooperates with Hda1p and Rpd3p to establish or maintain an extensive array of strongly positioned, deacetylated nucleosomes over the FLO1 promoter and upstream region which inhibit histone acetylation, block Swi–Snf binding and prevent transcription. PMID:25106892

Fleming, Alastair B.; Beggs, Suzanne; Church, Michael; Tsukihashi, Yoshihiro; Pennings, Sari

2014-01-01

321

The yeast Cyc8-Tup1 complex cooperates with Hda1p and Rpd3p histone deacetylases to robustly repress transcription of the subtelomeric FLO1 gene.  

PubMed

We demonstrate that the yeast flocculation gene, FLO1, is representative of a distinct subset of subtelomeric genes that are robustly repressed by the Cyc8-Tup1 complex. We have examined Cyc8-Tup1 localisation, histone acetylation and long-range chromatin remodelling within the extensive FLO1 upstream region. We show that Cyc8-Tup1 is localised in a DNase I hypersensitive site within an ordered array of strongly positioned nucleosomes around -700 base pairs upstream of the transcription start site. In cyc8 deletion mutant strains, Tup1p localisation is absent, with concomitant histone hyperacetylation of adjacent regions at the FLO1 promoter. This is accompanied by extensive histone depletion across the upstream region and gene activation. The yeast histone deacetylases, Hda1p and Rpd3p, occupy the repressed FLO1 promoter region in a Cyc8-Tup1 dependent manner and coordinate histone deacetylation, nucleosome stabilisation and gene repression. Moreover, we show that the ATP-dependent chromatin remodelling complex Swi-Snf occupies the site vacated by Cyc8-Tup1 in a cyc8 mutant. These data suggest that distinctly bound Cyc8-Tup1 cooperates with Hda1p and Rpd3p to establish or maintain an extensive array of strongly positioned, deacetylated nucleosomes over the FLO1 promoter and upstream region which inhibit histone acetylation, block Swi-Snf binding and prevent transcription. PMID:25106892

Fleming, Alastair B; Beggs, Suzanne; Church, Michael; Tsukihashi, Yoshihiro; Pennings, Sari

2014-11-01

322

Genetics Home Reference: Recombinant 8 syndrome  

MedlinePLUS

... understanding recombinant 8 syndrome? autosomal ; autosomal dominant ; cell ; chromosome ; cryptorchidism ; deletion ; disability ; DNA ; duplication ; gingival ; gums ; hyperplasia ; hypertelorism ; incidence ; ...

323

A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment  

PubMed Central

Background Kearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum. Case presentation Here, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years. Conclusions The response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death. PMID:23421922

2013-01-01

324

Role for cohesin in the formation of a heterochromatic domain at fission yeast subtelomeres.  

PubMed

Increasing evidence implicates cohesin in the control of gene expression. Here we report the first analysis of cohesin-dependent gene regulation in fission yeast. Global expression profiling of the mis4-367 cohesin loader mutant identified a small number of upregulated and downregulated genes within subtelomeric domains (SD). These 20- to 40-kb regions between chromosome arm euchromatin and telomere-proximal heterochromatin are characterized by a combination of euchromatin (methylated lysine 4 on histone H3/methylated Tysine 9 on histone H3 [H3K4me]) and heterochromatin (H3K9me) marks. We focused our analysis on the chromosome 1 right SD, which contains several upregulated genes and is bordered on the telomere-distal side by a pair of downregulated genes. We find that the expression changes in the SD also occur in a mutant of the cohesin core component Rad21. Remarkably, mutation of Rad21 results in the depletion of Swi6 binding in the SD. In fact, the Rad21 mutation phenocopied Swi6 loss of function: both mutations led to reduced cohesin binding, reduced H3K9me, and similar gene expression changes in the SD. In particular, expression of the gene pair bordering the SD was dependent both on cohesin and on Swi6. Our data indicate that cohesin participates in the setup of a subtelomeric heterochromatin domain and controls the expression of the genes residing in that domain. PMID:21189291

Dheur, Sonia; Saupe, Sven J; Genier, Sylvie; Vazquez, Stéphanie; Javerzat, Jean-Paul

2011-03-01

325

Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome.  

PubMed

Kabuki syndrome is a rare, multiple congenital anomaly/mental retardation syndrome caused by MLL2 point mutations and KDM6A microdeletions. We screened a large cohort of MLL2 mutation-negative patients for MLL2 and KDM6A exon(s) microdeletion and microduplication. Our assays failed to detect such rearrangements in MLL2 as well as in KDM6A gene. These results show that these genomic events are extremely rare in the Kabuki syndrome, substantiating its genetic heterogeneity and the search for additional causative gene(s). PMID:22840376

Priolo, Manuela; Micale, Lucia; Augello, Bartolomeo; Fusco, Carmela; Zucchetti, Federica; Prontera, Paolo; Paduano, Valeria; Biamino, Elisa; Selicorni, Angelo; Mammì, Corrado; Laganà, Carmelo; Zelante, Leopoldo; Merla, Giuseppe

2012-11-01

326

Perfect endings: a review of subtelomeric probes and their use in clinical diagnosis  

PubMed Central

Chromosomal rearrangements involving the ends of chromosomes (telomeres) are emerging as an important cause of human genetic diseases. This review describes the development of first and second generation sets of telomere specific clones, together with advances in fluorescence in situ hybridisation (FISH) technology, which have made the prospect of screening for telomeric rearrangements a realistic goal. Initial FISH studies using the telomere specific clones indicate that they will be a valuable diagnostic tool for the investigation of mental retardation, the characterisation of known abnormalities detected by conventional cytogenetic analysis, spontaneous recurrent miscarriages, infertility, haematological malignancies, and preimplantation diagnosis, as well as other fields of clinical interest. In addition, they may help investigate telomere structure and function and can be used in the identification of dosage sensitive genes involved in human genetic disease.???Keywords: subtelomeric probes; telomeres; FISH PMID:10851249

Knight, S.; Flint, J.

2000-01-01

327

The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17.  

PubMed Central

The human gene for cystathionine beta-synthase (CBS), the enzyme deficient in classical homocystinuria, has been assigned to the subtelomeric region of band 21q22.3 by in situ hybridization of a rat cDNA probe to structurally rearranged chromosomes 21. The homologous locus in the mouse (Cbs) was mapped to the proximal half of mouse chromosome 17 by Southern analysis of Chinese hamster X mouse somatic cell hybrid DNA. Thus, CBS/Cbs and the gene for alpha A-crystalline (CRYA1/Crya-1 or Acry-1) form a conserved linkage group on human (HSA) chromosome region 21q22.3 and mouse (MMU) chromosome 17 region A-C. Features of Down syndrome (DS) caused by three copies of these genes should not be present in mice trisomic for MMU 16 that have been proposed as animal models for DS. Mice partially trisomic for MMU 16 or MMU 17 should allow gene-specific dissection of the trisomy 21 phenotype. Images Figure 1 Figure 2 Figure 4 PMID:2894761

Münke, M; Kraus, J P; Ohura, T; Francke, U

1988-01-01

328

A protosilencer of subtelomeric gene expression in Candida glabrata with unique properties.  

PubMed

Adherence to host cells is an important step in the pathogenicity of the opportunistic fungal pathogen Candida glabrata. This adherence is mediated by some members of the large family of cell wall proteins encoded by the EPA (Epithelial Adhesin) genes present in the C. glabrata genome. The majority of the EPA genes are localized close to different telomeres in C. glabrata, resulting in a negative regulation of transcription of these genes through chromatin-based subtelomeric silencing. In vitro, adherence to epithelial cells is mainly mediated by Epa1, the only member of the EPA family that is expressed in vitro. EPA1 forms a cluster with EPA2 and EPA3 at the subtelomeric region of telomere E(-R). EPA2 and EPA3 are subject to silencing that propagates from this telomere in a process that depends on the Sir2, -3, -4, and Rif1 proteins, but surprisingly not on the yKu70 and yKu80 proteins. Here we describe that the yKu70/yKu80-independent silencing of telomere E(-R) is due to the presence of a cis-acting protosilencer (Sil2126) located between EPA3 and the telomere. This element can silence a reporter gene when placed 31.9 kb away from this telomere, but not when it is removed from the telomere context, or when it is placed near other telomeres, or inverted with respect to the reporter. Importantly, we show that the cis-acting Sil2126 element is required for the yKu70/80-independent silencing of this telomere, underscoring the importance of cis-elements for repressive chromatin formation and spreading on some telomeres in C. glabrata. PMID:22048024

Juárez-Reyes, Alejandro; Ramírez-Zavaleta, Candy Y; Medina-Sánchez, Luis; De Las Peñas, Alejandro; Castaño, Irene

2012-01-01

329

DNA Break Site at Fragile Subtelomeres Determines Probability and Mechanism of Antigenic Variation in African Trypanosomes  

PubMed Central

Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by ‘70 bp’-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in ‘active-site’ survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (?60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, ?H2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome. PMID:23555264

Glover, Lucy; Alsford, Sam; Horn, David

2013-01-01

330

DNA break site at fragile subtelomeres determines probability and mechanism of antigenic variation in African trypanosomes.  

PubMed

Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by '70 bp'-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in 'active-site' survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (?60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, ?H2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome. PMID:23555264

Glover, Lucy; Alsford, Sam; Horn, David

2013-03-01

331

Gomez-Lopez-Hernandez syndrome (cerebello-trigeminal-dermal dysplasia): description of an additional case and review of the literature.  

PubMed

Gomez-Lopez-Hernandez syndrome is a very rare genetic disorder with a distinct phenotype (OMIM 601853). To our knowledge there have been seven cases documented to date. We report on an additional male patient now aged 15 8/12 years with synostosis of the lambdoid suture, partial scalp alopecia, corneal opacity, mental retardation and striking phenotypic features (e.g., brachyturricephaly, hypertelorism, midface hypoplasia and low-set ears) consistent with Gomez-Lopez-Hernandez syndrome. In early childhood the patient demonstrated aggressive behavior and raging periods. He also had seizures that were adequately controlled by medication. Magnetic resonance imaging (MRI) revealed rhombencephalosynapsis, i.e., a rare fusion of the cerebellar hemispheres, also consistent with Gomez-Lopez-Hernandez syndrome. In addition a lipoma of the quadrigeminal plate was observed, a feature not previously described in the seven patients reported in the literature. Cytogenetic and subtelomere analyses were inconspicuous. Microarray-based comparative genomic hybridization (array-CGH) testing revealed five aberrations (partial deletions of 1p21.1, 8q24.23, 10q11.2, Xq26.3 and partial duplication of 19p13.2), which, however, have been classified as normal variants. Array-CGH has not been published in the previously reported children. The combination of certain craniofacial features, including partial alopecia, and the presence of rhombencephalosynapsis in the MRI are suggestive of Gomez-Lopez-Hernandez syndrome. Children with this syndrome should undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investingation, psychological testing, management of behavioral problems and genetic counseling. PMID:17483961

Schell-Apacik, Chayim Can; Cohen, Monika; Vojta, Stepan; Ertl-Wagner, Birgit; Klopocki, Eva; Heinrich, Uwe; von Voss, Hubertus

2008-01-01

332

Microhomology-mediated deletion and gene conversion in African trypanosomes.  

PubMed

Antigenic variation in African trypanosomes is induced by DNA double-strand breaks (DSBs). In these protozoan parasites, DSB repair (DSBR) is dominated by homologous recombination (HR) and microhomology-mediated end joining (MMEJ), while non-homologous end joining (NHEJ) has not been reported. To facilitate the analysis of chromosomal end-joining, we established a system whereby inter-allelic repair by HR is lethal due to loss of an essential gene. Analysis of intrachromosomal end joining in individual DSBR survivors exclusively revealed MMEJ-based deletions but no NHEJ. A survey of microhomologies typically revealed sequences of between 5 and 20?bp in length with several mismatches tolerated in longer stretches. Mean deletions were of 54?bp on the side closest to the break and 284?bp in total. Break proximity, microhomology length and GC-content all favored repair and the pattern of MMEJ described above was similar at several different loci across the genome. We also identified interchromosomal gene conversion involving HR and MMEJ at different ends of a duplicated sequence. While MMEJ-based deletions were RAD51-independent, one-sided MMEJ was RAD51 dependent. Thus, we describe the features of MMEJ in Trypanosoma brucei, which is analogous to micro single-strand annealing; and RAD51 dependent, one-sided MMEJ. We discuss the contribution of MMEJ pathways to genome evolution, subtelomere recombination and antigenic variation. PMID:20965968

Glover, Lucy; Jun, Junho; Horn, David

2011-03-01

333

The putative imprinted locus D15S9 within the common deletion region for the Prader-Willi and Angelman syndromes encodes two overlapping mRNAs transcribed from opposite strands  

SciTech Connect

Prader-Willi syndrome is typically caused by a deletion of paternal 15q11-q13, or maternal uniparental disomy (UPD) of chromosome 15, while Angelman syndrome is caused by a maternal deletion or paternal UPD of the same region. Therefore, these two clinically distinct neurobehavioral syndromes result from differential expression of imprinted genes within 15q11-q13. A 3.1 kb cDNA, DN34, from the D15S9 locus within 15q11-q13 was isolated from a human fetal brain library. We showed previously that DN34 probe detects a DNA methylation imprint and therefore may represent a candidate imprinted gene. Isolation of genomic clones and DNA sequencing demonstrated that the gene segment encoding the partial cDNA DN34 was split by a 2 kb intron, but did not encode a substantial open reading frame (ORF). Preliminary analysis of expression by RT-PCR suggests that this gene is expressed in fetal but not in tested tissue types from the adult, and thus its imprinting status has not been possible to assess at present. Surprisingly, we found an ORF on the antisense strand of the DN34 cDNA. This ORF encodes a putative polypeptide of 505 amino acid residues containing a RING C{sub 3}HC{sub 4} zinc-finger motif and other features of nuclear proteins. Subsequent characterization of this gene, ZNF127, and a mouse homolog, demonstrated expression of 3.2 kb transcript from all tested fetal and adult tissues. Transcripts initiate from within a CpG-island, shown to be differentially methylated on parental alleles in the human. Interestingly, functional imprinting of the mouse homolog was subsequently demonstrated in an F{sub 1} cross by analyzing a VNTR polymorphism in the mRNA. The ZNF127 gene is intronless, has significant overlap with the DN34 gene on the antisense strand, and a 1 kb 3{prime} end within the 2 kb DN34 intron.

Glenn, C.C.; Driscoll, D.J. [Univ. of Florida, Gainesville, FL (United States); Saitoh, S. [Case Western Reserve Univ., Cleveland, OH (United States)] [and others

1994-09-01

334

The Deacetylase Sir2 from the Yeast Clavispora lusitaniae Lacks the Evolutionarily Conserved Capacity to Generate Subtelomeric Heterochromatin  

PubMed Central

Deacetylases of the Sir2 or sirtuin family are thought to regulate life cycle progression and life span in response to nutrient availability. This family has undergone successive rounds of duplication and diversification, enabling the enzymes to perform a wide variety of biological functions. Two evolutionarily conserved functions of yeast Sir2 proteins are the generation of repressive chromatin in subtelomeric domains and the suppression of unbalanced recombination within the tandem rDNA array. Here, we describe the function of the Sir2 ortholog ClHst1 in the yeast Clavispora lusitaniae, an occasional opportunistic pathogen. ClHst1 was localized to the non-transcribed spacer regions of the rDNA repeats and deacetylated histones at these loci, indicating that, like other Sir2 proteins, ClHst1 modulates chromatin structure at the rDNA repeats. However, we found no evidence that ClHst1 associates with subtelomeric regions or impacts gene expression directly. This surprising observation highlights the plasticity of sirtuin function. Related yeast species, including Candida albicans, possess an additional Sir2 family member. Thus, it is likely that the ancestral Candida SIR2/HST1 gene was duplicated and subfunctionalized, such that HST1 retained the capacity to regulate rDNA whereas SIR2 had other functions, perhaps including the generation of subtelomeric chromatin. After subsequent species diversification, the SIR2 paralog was apparently lost in the C. lusitaniae lineage. Thus, C. lusitaniae presents an opportunity to discover how subtelomeric chromatin can be reconfigured. PMID:24204326

Froyd, Cara A.; Kapoor, Shivali; Dietrich, Fred; Rusche, Laura N.

2013-01-01

335

Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization.  

PubMed

The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ hybridization techniques, we have found that specific telomeres have preferential time windows for replication during the S-phase and that these intervals do not depend upon telomere length and are largely conserved between homologous chromosomes and between individuals, even in the presence of large subtelomeric segmental polymorphisms. Importantly, we show that one copy of the 3.3 kb macrosatellite repeat D4Z4, present in the subtelomeric region of the late replicating 4q35 telomere, is sufficient to confer both a more peripheral localization and a later-replicating property to a de novo formed telomere. Also, the presence of beta-satellite repeats next to a newly created telomere is sufficient to delay its replication timing. Remarkably, several native, non-D4Z4-associated, late-replicating telomeres show a preferential localization toward the nuclear periphery, while several early-replicating telomeres are associated with the inner nuclear volume. We propose that, in humans, chromosome arm-specific subtelomeric sequences may influence both the spatial distribution of telomeres in the nucleus and their replication timing. PMID:20421929

Arnoult, Nausica; Schluth-Bolard, Caroline; Letessier, Anne; Drascovic, Irena; Bouarich-Bourimi, Rachida; Campisi, Judith; Kim, Sahn-Ho; Boussouar, Amina; Ottaviani, Alexandre; Magdinier, Frédérique; Gilson, Eric; Londoño-Vallejo, Arturo

2010-04-01

336

Post vaccine acute disseminated encephalomyelitis as the first manifestation of chromosome 22q11.2 deletion syndrome in a 15-month old baby: a case report.  

PubMed

We describe a case of a 15-month-old female child admitted to our hospital because of fever, rash, neurological signs (oscillation between states of irritability and drowsiness), palpebral edema and drooping eyelid, appeared 10 days after the vaccination for measles, mumps and rubella. Brain MRI images showed multiple bilateral hyperintense lesions in the white matter typical of acute disseminated encephalomyelitis (ADEM), an autoimmune demyelinating disorder with inflammatory lesions of the central nervous system, due to viral antigens or vaccines. In the mean time, because of patient's vague phenotypic manifestations, suggestive of a genetic defect, array comparative genomic hybridization was carried out which showed the presence of a microdeletion 22q11.21, linked to the DiGeorge syndrome. Our case suggests that pediatric cases of post-vaccination ADEM, in which neurological signs persist, should be investigated for genetic phenotypical features, in order to exclude the presence of a genetic syndrome or disease. PMID:25171844

Valenzise, Mariella; Cascio, Antonio; Wasniewska, Malgorzata; Zirilli, Giuseppina; Catena, Maria Ausilia; Arasi, Stefania

2014-09-29

337

Diagnosis of 22q11.2 deletion syndrome and artemis deficiency in two children with T-B-NK+ immunodeficiency.  

PubMed

Two infants are described who presented with 22q11.2 deletion and a T(-)B(-)NK(+) immune phenotype. For both infants, the initial diagnosis was athymia secondary to complete DiGeorge anomaly. The first infant underwent thymus transplantation but 6 months after transplantation had circulating thymus donor T cells; the patient did not develop recipient naïve T cells. Genetic analyses revealed that both patients had Artemis deficiency, a rare form of severe combined immunodeficiency (SCID). Both infants have subsequently undergone bone marrow transplantation. These cases illustrate the importance and paradox of differentiating SCID from complete DiGeorge anomaly because hematopoietic stem cell transplantation (HSCT) is the preferred treatment for SCID but is ineffective for complete DiGeorge anomaly. However, if the thymus is completely absent, donor stem cells from a HSCT would not be able to be educated. PMID:22864628

Heimall, Jennifer; Keller, Michael; Saltzman, Rushani; Bunin, Nancy; McDonald-McGinn, Donna; Zakai, Elaine; de Villartay, Jean-Pierre; Moshous, Despina; Ariue, Barbara; McCarthy, Elizabeth A; Devlin, Blythe H; Parikh, Suhag; Buckley, Rebecca H; Markert, M Louise

2012-10-01

338

Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGG repeat-binding activity.  

PubMed

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immune response. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown that telomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly more VSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, which folds into a canonical helix-loop-helix structure that is conserved to the Myb domains of mammalian TRF proteins. The TbTRF Myb domain tolerates well the bulky J base in T. brucei telomere DNA, and the DNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, we find that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinity also led to significantly increased VSG switching frequencies, indicating that the telomere DNA-binding activity is critical for TbTRF's role in VSG switching regulation. PMID:25313155

Jehi, Sanaa E; Li, Xiaohua; Sandhu, Ranjodh; Ye, Fei; Benmerzouga, Imaan; Zhang, Mingjie; Zhao, Yanxiang; Li, Bibo

2014-11-10

339

Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGG repeat-binding activity  

PubMed Central

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immune response. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown that telomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly more VSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, which folds into a canonical helix-loop-helix structure that is conserved to the Myb domains of mammalian TRF proteins. The TbTRF Myb domain tolerates well the bulky J base in T. brucei telomere DNA, and the DNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, we find that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinity also led to significantly increased VSG switching frequencies, indicating that the telomere DNA-binding activity is critical for TbTRF's role in VSG switching regulation. PMID:25313155

Jehi, Sanaa E.; Li, Xiaohua; Sandhu, Ranjodh; Ye, Fei; Benmerzouga, Imaan; Zhang, Mingjie; Zhao, Yanxiang; Li, Bibo

2014-01-01

340

Precise sequence complementarity between yeast chromosome ends and two classes of just-subtelomeric sequences.  

PubMed

The terminal regions (last 20 kb) of Saccharomyces cerevisiae chromosomes universally contain blocks of precise sequence similarity to other chromosome terminal regions. The left and right terminal regions are distinct in the sense that the sequence similarities between them are reverse complements. Direct sequence similarity occurs between the left terminal regions and also between the right terminal regions, but not between any left ends and right ends. With minor exceptions the relationships range from 80% to 100% match within blocks. The regions of similarity are composites of familiar and unfamiliar repeated sequences as well as what could be considered "single-copy" (or better "two-copy") sequences. All terminal regions were compared with all other chromosomes, forward and reverse complement, and 768 comparisons are diagrammed. It appears there has been an extensive history of sequence exchange or copying between terminal regions. The subtelomeric sequences fall into two classes. Seventeen of the chromosome ends terminate with the Y' repeat, while 15 end with the 800-nt "X2" repeats just adjacent to the telomerase simple repeats. The just-subterminal repeats are very similar to each other except that chromosome 1 right end is more divergent. PMID:9600891

Britten, R J

1998-05-26

341

DNA-end capping by the budding yeast transcription factor and subtelomeric binding protein Tbf1  

PubMed Central

Telomere repeats in budding yeast are maintained at a constant average length and protected (‘capped'), in part, by mechanisms involving the TG1?3 repeat-binding protein Rap1. However, metazoan telomere repeats (T2AG3) can be maintained in yeast through a Rap1-independent mechanism. Here, we examine the dynamics of capping and telomere formation at an induced DNA double-strand break flanked by varying lengths of T2AG3 repeats. We show that a 60-bp T2AG3 repeat array induces a transient G2/M checkpoint arrest, but is rapidly elongated by telomerase to generate a stable T2AG3/TG1–3 hybrid telomere. In contrast, a 230-bp T2AG3 array induces neither G2/M arrest nor telomerase elongation. This capped state requires the T2AG3-binding protein Tbf1, but is independent of two Tbf1-interacting factors, Vid22 and Ygr071c. Arrays of binding sites for three other subtelomeric or Myb/SANT domain-containing proteins fail to display a similar end-protection effect, indicating that Tbf1 capping is an evolved function. Unexpectedly, we observed strong telomerase association with non-telomeric ends, whose elongation is blocked by a Mec1-dependent mechanism, apparently acting at the level of Cdc13 binding. PMID:21952045

Ribaud, Virginie; Ribeyre, Cyril; Damay, Pascal; Shore, David

2012-01-01

342

Schizophrenia Susceptibility Associated with Interstitial Deletions of Chromosome 22q11  

Microsoft Academic Search

We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22q11 in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated

Maria Karayiorgou; Michael A. Morris; Bernice Morrow; Robert J. Shprintzen; Rosalie Goldberg; Julian Borrow; Arnaud Gos; Gerald Nestadt; Paula S. Wolyniec; Virginia K. Lasseter; Harvey Eisen; Barton Childs; Haig H. Kazazian; Raju Kucherlapati; Stylianos E. Antonarakis; Ann E. Pulver; David E. Housman

1995-01-01

343

Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice.  

PubMed

Usher syndrome type 2 (USH2) is the predominant form of USH, a leading genetic cause of combined deafness and blindness. PDZD7, a paralog of two USH causative genes, USH1C and USH2D (WHRN), was recently reported to be implicated in USH2 and non-syndromic deafness. It encodes a protein with multiple PDZ domains. To understand the biological function of PDZD7 and the pathogenic mechanism caused by PDZD7 mutations, we generated and thoroughly characterized a Pdzd7 knockout mouse model. The Pdzd7 knockout mice exhibit congenital profound deafness, as assessed by auditory brainstem response, distortion product otoacoustic emission and cochlear microphonics tests, and normal vestibular function, as assessed by their behaviors. Lack of PDZD7 leads to the disorganization of stereocilia bundles and a reduction in mechanotransduction currents and sensitivity in cochlear outer hair cells. At the molecular level, PDZD7 determines the localization of the USH2 protein complex, composed of USH2A, GPR98 and WHRN, to ankle links in developing cochlear hair cells, likely through its direct interactions with these three proteins. The localization of PDZD7 to the ankle links of cochlear hair bundles also relies on USH2 proteins. In photoreceptors of Pdzd7 knockout mice, the three USH2 proteins largely remain unchanged at the periciliary membrane complex. The electroretinogram responses of both rod and cone photoreceptors are normal in knockout mice at 1 month of age. Therefore, although the organization of the USH2 complex appears different in photoreceptors, it is clear that PDZD7 plays an essential role in organizing the USH2 complex at ankle links in developing cochlear hair cells. GenBank accession numbers: KF041446, KF041447, KF041448, KF041449, KF041450, KF041451. PMID:24334608

Zou, Junhuang; Zheng, Tihua; Ren, Chongyu; Askew, Charles; Liu, Xiao-Ping; Pan, Bifeng; Holt, Jeffrey R; Wang, Yong; Yang, Jun

2014-05-01

344

Genetic obesity syndromes.  

PubMed

There are numerous reports of multi-system genetic disorders with obesity. Many have a characteristic presentation and several, an overlapping phenotype indicating the likelihood of a shared common underlying mechanism or pathway. By understanding the genetic causes and functional perturbations of such syndromes we stand to gain tremendous insight into obesogenic pathways. In this review we focus particularly on Bardet-Biedl syndrome, whose molecular genetics and cell biology has been elucidated recently, and Prader-Willi syndrome, the commonest obesity syndrome due to loss of imprinted genes on 15q11-13. We also discuss highlights of other genetic obesity syndromes including Alstrom syndrome, Cohen syndrome, Albright's hereditary osteodystrophy (pseudohypoparathyroidism), Carpenter syndrome, MOMO syndrome, Rubinstein-Taybi syndrome, cases with deletions of 6q16, 1p36, 2q37 and 9q34, maternal uniparental disomy of chromosome 14, fragile X syndrome and Börjeson-Forssman-Lehman syndrome. PMID:18230893

Goldstone, Anthony P; Beales, Philip L

2008-01-01

345

A comparative analysis of the composition and organization of two subtelomeric repeat families in Aegilops speltoides Tausch. and related species.  

PubMed

The structural organization and evolution of two tandemly repeated families, Spelt1 and Spelt52, located in the subtelomeric regions of Aegilops speltoides chromosomes were studied. The Spelt1 family of sequences with a monomer length of 178 bp was characterized by cloning and sequence analysis of polymerase chain reaction (PCR) products. Members of the Spelt1 family revealed sequence similarities exceeding 95%. This conservation has remained despite divergence of species in Aegilops section Sitopsis and after independent multiple amplification events in the genome of Ae. speltoides. Sequences representing the Spelt52 family were cloned, sequenced and compared with other sequences in databases. The Spelt52 repeat family contains monomers of two types, Spelt52.1 and Spelt52.2. The two monomers share a homologous stretch of 280 bp and have two regions without sequence similarity of 96 bp and 110 bp, respectively. PCR analysis was conducted to 15 lines in Ae. speltoides Tausch., Ae. longissima Schw. & Mushc., Ae. sharonensis Eig., Ae. bicornis (Forssk) Jaub.&Sp., and Ae. searsii Feld.&Kis. using primers to the homologous and nonhomologous regions of Spelt52 family. Intraspecies and interspecies differences in the occurrence and abundance of combinations of Spelt52.1 and Spelt52.2 monomers were detected. The use of primers to telomeric and subtelomeric repeats followed by Southern hybridization, cloning, and sequence analysis demonstrated that Spelt1 and Spelt52 are localized close to each other and to telomeric repeats. The efficiency of a PCR approach for the analysis of telomeric/subtelomeric junction regions of chromosomes is discussed. PMID:15609545

Salina, E A; Adonina, I G; Vatolina, T Yu; Kurata, N

2004-11-01

346

What Causes Rett Syndrome?  

MedlinePLUS

... www.ncbi.nlm.nih.gov/pubmed/15917271 [top] Jacob, F. D., Ramaswamy, V., Andersen, J., & Bolduc, F. V. (2009). Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic ...

347

Long-term outcome of anemic lower-risk myelodysplastic syndromes without 5q deletion refractory to or relapsing after erythropoiesis-stimulating agents.  

PubMed

A large proportion of lower-risk myelodysplastic syndromes (MDS) respond to erythropoiesis-stimulating agents (ESA), but most responses are transient. We updated a previously reported cohort of lower-risk MDS patients treated with ESA and analyzed outcomes after ESA failure. In 120 patients with primary resistance and 66 patients with relapse after an initial response to ESA, the 5-year cumulative incidence of acute myeloid leukemia (AML) after failure was 18.9% and 11.6%, respectively (P=0.20). Median overall survival (OS) after failure was 40.1 and 44.9 months (P=0.35), respectively. We further categorized patients as 'early failures' (including resistance and relapse after <6 months of response), or 'later failures' (that is, relapse after ?6 months). The 5-year cumulative incidence of AML and median OS after failure in early and later failure were 21.6% and 9% (P=0.02) and 36.7 and 54.3 months (P=0.02), respectively. Early failure to ESA and a baseline diagnosis of refractory anemia with excess blasts (RAEB)-1 were independent prognostic factors for AML progression and, along with trisomy 8, for shorter OS. Median OS from treatment onset was 40, 90.7 and 65.8 months in early failure, later failure and no relapse, respectively (P=0.001). Lower-risk MDS with early failure to ESA have a relatively unfavorable outcome, and should be offered alternative treatments. PMID:23370672

Kelaidi, C; Park, S; Sapena, R; Beyne-Rauzy, O; Coiteux, V; Vey, N; Stamatoullas, A; Choufi, B; Delaunay, J; Gourin, M-P; Cheze, S; Ravoet, C; Ferrant, A; Escoffre-Barbe, M; Aljassem, L; Raffoux, E; Itzykson, R; Adès, L; Dreyfus, F; Fenaux, P

2013-06-01

348

A novel immunodeficiency syndrome associated with partial trisomy 19p13  

PubMed Central

Background Subtelomeric deletions and duplications may cause syndromic disorders that include features of immunodeficiency. To date, no phenotype of immunological pathology has been linked to partial trisomy 19. We report here on two unrelated male patients showing clinical and laboratory signs of immunodeficiency exhibiting a duplication involving Chromosome 19p13. Methods Both patients underwent a detailed clinical examination. Extended laboratory investigations for immune function, FISH and array comparative genome hybridization (CGH) analyses were performed. Results The reported patients were born prematurely with intrauterine growth retardation and share clinical features including neurological impairment, facial dysmorphy and urogenital malformations. Array CGH analyses of both patients showed a largely overlapping terminal duplication affecting Chromosome 19p13. In both affected individuals, the clinical course was marked by recurrent severe infections. Signs of humoral immunodeficiency were detected, including selective antibody deficiency against polysaccharide antigens in patient 1 and reduced IgG1, IgG3 subclass levels and IgM deficiency in patient 2. Class-switched B memory cells were almost absent in both patients. Normal numbers of T cells, B cells and natural killer cells were observed in both boys. Lymphocytic proliferation showed no consistent functional pathology, however, function of granulocytes and monocytes as assessed by oxidative burst test was moderately reduced. Moreover, natural killer cytotoxicity was reduced in both patients. Immunoglobulin substitution resulted in a decreased number and severity of infections and improved thriving in both patients. Conclusions Partial trisomy 19p13 represents a syndromic disorder associating organ malformation and hitherto unrecognised immunodeficiency. PMID:24431329

Seidel, Markus G; Duerr, Celia; Woutsas, Stavroula; Schwerin-Nagel, Anette; Sadeghi, Kambis; Neesen, Jürgen; Uhrig, Sabine; Santos-Valente, Elisangela; Pickl, Winfried F; Schwinger, Wolfgang; Urban, Christian; Boztug, Kaan; Förster-Waldl, Elisabeth

2014-01-01

349

Replication Timing of Human Telomeres Is Chromosome Arm–Specific, Influenced by Subtelomeric Structures and Connected to Nuclear Localization  

E-print Network

The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ hybridization techniques, we have found that specific telomeres have preferential time windows for replication during the S-phase and that these intervals do not depend upon telomere length and are largely conserved between homologous chromosomes and between individuals, even in the presence of large subtelomeric segmental polymorphisms. Importantly, we show that one copy of the 3.3 kb macrosatellite repeat D4Z4, present in the subtelomeric region of the late replicating 4q35 telomere, is sufficient to confer both a more peripheral localization and a later-replicating property to a de novo formed telomere. Also, the presence of b-satellite repeats next to a newly created telomere is sufficient to delay its replication timing. Remarkably, several native, non-D4Z4– associated, late-replicating telomeres show a preferential localization toward the nuclear periphery, while several earlyreplicating telomeres are associated with the inner nuclear volume. We propose that, in humans, chromosome arm–specific

Nausica Arnoult; Caroline Schluth-bolard; Anne Letessier; Irena Drascovic; Judith Campisi; Sahn-ho Kim; Amina Boussouar; Re Ottaviani; Frédérique Magdinier; Eric Gilson; Arturo Londoño-vallejo

350

The motor profile of primary school-age children with a 22q11.2 deletion syndrome (22q11.2DS) and an age- and IQ-matched control group.  

PubMed

In the early publications on the 22q11.2 Deletion Syndrome (22q11.2DS) motor abnormalities have been frequently reported. However, systematic studies on the motor performance of children with the 22q11.2DS, and especially of school-age children, are scarce. In this study the motor performance of primary school-age children with a 22q11.2DS (n = 28) was compared with an age- and IQ-matched control group (n = 28) using the Movement Assessment Battery for Children (MABC), the Körperkoordinationstest für Kinder (KTK) and the Beery-Buctenica test of Visual-Motor Integration (Beery). Children with a 22q11.2DS scored significantly lower than the age- and IQ-matched control group on the subsection Manual Dexterity (MABC) and the Visual Perception and Motor Coordination subtests of the Beery. When investigating the correlations between Intelligence quotient (IQ) and motor performance, a specific profile was found in the 22q11.2DS group when compared with the age- and IQ-matched control group. Because an IQ-matched control group was adopted, the deficits in visual-perceptual and visuomotor integration skills cannot fully be attributed to a general developmental delay and thus may be specific for the 22q11.2DS. Future studies that investigate the specificity of the visual-perceptual problems - both on the behavioral and brain level (functional Magnetic Resonance Imaging [fMRI] and Diffusion Tensor Imaging [DTI]) - are necessary to answer this question. Nonetheless, the importance of incorporating motor functioning into the study of the neuropsychological profile of children with a 22q11.2DS has to be stressed. PMID:19280375

Van Aken, Katrijn; Caeyenberghs, Karen; Smits-Engelsman, Bouwien; Swillen, Ann

2009-11-01

351

Genetics Home Reference: FOXG1 syndrome  

MedlinePLUS

... cerebrum), which controls most voluntary activity, language, sensory perception, learning, and memory. In some cases, FOXG1 syndrome ... callosum ; deletion ; disability ; embryonic ; encephalopathy ; gene ; involuntary ; microcephaly ; perception ; protein ; spectrum ; syndrome ; tissue ; white matter You may ...

352

Cytogenetic and molecular characterization of a three-generation family with chromosome 5p terminal deletion.  

PubMed

Terminal or interstitial deletion on the short arm of chromosome 5 is associated with a genetic disorder, cri-du-chat syndrome (cat cry syndrome), which is characterized by a cat-like cry in infancy, facial dysmorphism, microcephaly, and mental retardation. There is a high degree of variation in clinical presentations of patients with cri-du-chat syndrome, which is usually associated with different sizes and locations of deletions in chromosome 5p. Most patients with a 5p deletion have de novo mutations; familial 5p deletion is rare in literature. Here, we report a three-generation family with a 5p terminal deletion. The terminal 5p deletion (5p15.2-pter) in this family was confirmed and characterized by karyotyping analysis, fluorescent in situ hybridization, array comparative genome hybridization, and quantitative polymerase chain reaction. Although the affected family members apparently share deletions of the same size, there are some variations in mental symptoms within this family. Two affected females manifest moderate mental retardation and psychotic symptoms such as delusion of persecution, auditory hallucination, self-talking, and self-laughing, which are rare in cri-du-chat syndrome. In contrast, the other three affected males express mild-to-moderate mental retardation but no psychotic symptoms. Our study suggests that other factors besides the size and location of 5p deletions may modify the mental presentations of patients with 5p deletions. PMID:18400035

Fang, J-S; Lee, K-F; Huang, C-T; Syu, C-L; Yang, K-J; Wang, L-H; Liao, D-L; Chen, C-H

2008-06-01

353

Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS)  

PubMed Central

Background Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. Results Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000?mg or 2500?mg/day) in combination with 10?mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10?mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000?mg/10?mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10?mg doses recommended for future studies. Conclusions The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active. Trial registration Clinicaltrials.gov: NCT01062152 PMID:22546242

2012-01-01

354

Genetics Home Reference: 18q deletion syndrome  

MedlinePLUS

... pages Patient support For patients and families Gene Reviews Clinical summary PubMed Recent literature OMIM Genetic disorder catalog Conditions > 18q ... are designed for healthcare professionals and researchers. Gene Reviews - Clinical ... - Recent literature OMIM - Genetic disorder catalog What other ...

355

Phenotypes of AKT3 deletion: A case report and literature review.  

PubMed

AKT3 (v-akt murine thymoma viral oncogene homolog 3) is located at chromosome 1q44 and encodes a 479 amino acid protein, a member of the protein kinase B (PKB) family. This gene is frequently involved in 1q44 deletion syndrome in patients with microcephaly, intellectual disability, and dysmorphic features. Phenotype and genotype studies of patients with 1q44 deletion syndrome have suggested that deletion of the AKT3 gene is responsible for the microcephaly in these patients. However, the phenotype of pure AKT3 deletion has not been studied. We report on a 1q44 deletion involving only AKT3 in a boy and his father. The boy has microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features. His father does not have microcephaly and is of normal intelligence. We also analyzed the available information on the phenotypes of 13 individuals carrying a pure AKT3 gene deletion identified through literature review and database search. To our knowledge, this is the first report of a paternally inherited pure AKT3 deletion with full clinical description. This is also the first report to suggest that (1) AKT3 deletion is associated with microcephaly and intellectual disability with incomplete penetrance; (2) a pure AKT3 deletion is likely to be inherited in contrast to the larger 1q44 deletions, which are mostly de novo and (3) there seems to be no consistent or characteristic dysmorphism associated with pure AKT3 deletion. © 2014 Wiley Periodicals, Inc. PMID:25424989

Gai, Dayu; Haan, Eric; Scholar, Matthew; Nicholl, Jillian; Yu, Sui

2015-01-01

356

Addition deletion networks  

NASA Astrophysics Data System (ADS)

We study structural properties of growing networks where both addition and deletion of nodes are possible. Our model network evolves via two independent processes. With rate r, a node is added to the system and this node links to a randomly selected existing node. With rate 1, a randomly selected node is deleted and its parent node inherits the links of its immediate descendants. We show that the in-component size distribution decays algebraically, ck ~ k-? as k ? ?. The exponent ? = 2 + (r - 1)-1 varies continuously with the addition rate r. Structural properties of the network including the height distribution, the diameter of the network, the average distance between two nodes and the fraction of dangling nodes are also obtained analytically. Interestingly, the deletion process leads to a giant hub, a single node with a macroscopic degree whereas all other nodes have a microscopic degree.

Ben-Naim, E.; Krapivsky, P. L.

2007-07-01

357

Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study  

Microsoft Academic Search

We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and

A K Ryan; J A Goodship; D I Wilson; N Philip; A Levy; H Seidel; S Schuffenhauer; H Oechsler; B Belohradsky; M Prieur; A Aurias; F L Raymond; J Clayton-Smith; E Hatchwell; C McKeown; F A Beemer; B Dallapiccola; G Novelli; J A Hurst; J Ignatius; A J Green; R M Winter; L Brueton; K Brøndum-Nielsen; P J Scambler

1997-01-01

358

PAX3 gene deletion detected by microarray analysis in a girl with hearing loss  

PubMed Central

Deletions of the PAX3 gene have been rarely reported in the literature. Mutations of this gene are a common cause of Waardenburg syndrome type 1 and 3. We report a 16?year old female presenting hearing loss and normal intellectual development, without major features of Waardenburg syndrome type 1, and without family history of the syndrome. Her phenotype, however, overlaps with features of craniofacial-deafness-hand syndrome. Microarray analysis showed ~862?kb de novo deletion at 2q36.1 including PAX3. The above findings suggest that the rearrangement found in our patient appeared de novo and with high probability is a cause of her phenotype. PMID:24839464

2014-01-01

359

Genetic Counseling for the 22q11.2 Deletion  

ERIC Educational Resources Information Center

Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

McDonald-McGinn, Donna M.; Zackai, Elaine H.

2008-01-01

360

Genetic Modifiers of the Physical Malformations in Velo-Cardio-Facial Syndrome/DiGeorge Syndrome  

ERIC Educational Resources Information Center

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), the most common micro-deletion disorder in humans, is characterized by craniofacial, parathyroid, and thymic defects as well as cardiac outflow tract malformations. Most patients have a similar hemizygous 3 million base pair deletion on 22q11.2. Studies in mouse have shown that "Tbx1", a…

Aggarwal, Vimla S.; Morrow, Bernice E.

2008-01-01

361

Transmitted deletions of medial 5p and learning difficulties; does the cadherin cluster only become penetrant when flanking genes are deleted?  

PubMed

The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family. PMID:21965044

Barber, John C K; Huang, Shuwen; Bateman, Mark S; Collins, Amanda L

2011-11-01

362

Jacobsen syndrome  

PubMed Central

Jacobsen syndrome is a MCA/MR contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. To date, over 200 cases have been reported. The prevalence has been estimated at 1/100,000 births, with a female/male ratio 2:1. The most common clinical features include pre- and postnatal physical growth retardation, psychomotor retardation, and characteristic facial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, broad nasal bridge, short nose, v-shaped mouth, small ears, low set posteriorly rotated ears). Abnormal platelet function, thrombocytopenia or pancytopenia are usually present at birth. Patients commonly have malformations of the heart, kidney, gastrointestinal tract, genitalia, central nervous system and skeleton. Ocular, hearing, immunological and hormonal problems may be also present. The deletion size ranges from ~7 to 20 Mb, with the proximal breakpoint within or telomeric to subband 11q23.3 and the deletion extending usually to the telomere. The deletion is de novo in 85% of reported cases, and in 15% of cases it results from an unbalanced segregation of a familial balanced translocation or from other chromosome rearrangements. In a minority of cases the breakpoint is at the FRA11B fragile site. Diagnosis is based on clinical findings (intellectual deficit, facial dysmorphic features and thrombocytopenia) and confirmed by cytogenetics analysis. Differential diagnoses include Turner and Noonan syndromes, and acquired thrombocytopenia due to sepsis. Prenatal diagnosis of 11q deletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Management is multi-disciplinary and requires evaluation by general pediatrician, pediatric cardiologist, neurologist, ophthalmologist. Auditory tests, blood tests, endocrine and immunological assessment and follow-up should be offered to all patients. Cardiac malformations can be very severe and require heart surgery in the neonatal period. Newborns with Jacobsen syndrome may have difficulties in feeding and tube feeding may be necessary. Special attention should be devoted due to hematological problems. About 20% of children die during the first two years of life, most commonly related to complications from congenital heart disease, and less commonly from bleeding. For patients who survive the neonatal period and infancy, the life expectancy remains unknown. PMID:19267933

Mattina, Teresa; Perrotta, Concetta Simona; Grossfeld, Paul

2009-01-01

363

Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF.  

PubMed

The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome. PMID:19644448

Ottaviani, Alexandre; Schluth-Bolard, Caroline; Rival-Gervier, Sylvie; Boussouar, Amina; Rondier, Delphine; Foerster, Andrea M; Morere, Julia; Bauwens, Serge; Gazzo, Sophie; Callet-Bauchu, Evelyne; Gilson, Eric; Magdinier, Frédérique

2009-08-19

364

The phenotype associated with a large deletion on MECP2  

PubMed Central

Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22–0.79, P=0.007) and to be currently walking (OR 0.53, 95% CI: 0.26–1.10, P=0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98–3.48, P=0.057) and epilepsy (OR 2.72, 95% CI: 1.38–5.37, P=0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected. PMID:22473088

Bebbington, Ami; Downs, Jenny; Percy, Alan; Pineda, Mercé; Zeev, Bruria Ben; Bahi-Buisson, Nadia; Leonard, Helen

2012-01-01

365

Temperament in Velocardiofacial Syndrome  

ERIC Educational Resources Information Center

Background: Velocardiofacial syndrome (VCFS) is a microdeletion syndrome caused by a 22q11.2 chromosomal deletion. Methods: In this study, parents reported on their own temperament as well as the temperament of their child. Sixty-seven children with VCFS (mean age = 10.8, SD = 2.8; range 6-15), and age-, race- and gender-ratio matched samples of…

Antshel, K. M.; Stallone, K.; AbdulSabur, N.; Shprintzen, R.; Roizen, N.; Higgins, A. M.; Kates, W. R.

2007-01-01

366

A case of duplication of 13q32-->qter and deletion of 18p11.32-->pter with mild phenotype: Patau syndrome and duplications of 13q revisited  

Microsoft Academic Search

A mild clinical phenotype is described in a patient with duplication of 13q32-->qter and a small deletion of 18p11.32-->pter. The 8 year old white male presented with psychomotor retardation, tethered cord, soft, fleshy ears, and normal facial features except for thin lips. The karyotype was found to be 46, XY, der(18)t(13;18) (q32;p11.32) pat confirmed by fluorescence in situ hybridisation (FISH).

N Helali; A K Iafolla; S G Kahler; M B Qumsiyeh

1996-01-01

367

Distinct phenotype of PHF6 deletions in females.  

PubMed

We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation. PMID:24380767

Di Donato, N; Isidor, B; Lopez Cazaux, S; Le Caignec, C; Klink, B; Kraus, C; Schrock, E; Hackmann, K

2014-02-01

368

Deletion (X)(q26. 1[r arrow]q28) in a proband and her mother: Molecular characterization and phenotypic-karyotypic deductions  

SciTech Connect

During a routine pernatal diagnosis the authors detected a female fetus with an apparent terminal deletion of an X chromosome with a karyotype 46,X,del(X)(q25); the mother, who later underwent premature ovarian failure, had the same Xq deletion. To further delineate this familial X deletion and to determine whether the deletion was truly terminal or, rather, interstitial (retaining a portion of the terminal Xq28), the authors used a combination of fluorescence in situ hybridization (FISH) and Southern analyses. RFLP analyses and dosage estimation by densitometry were performed with a panel of nine probes (DXS3, DXS17, DXS11, DXS42, DXS86, DXS144E, DXS105, DXS304, and DXS52) that span the region Xq21 to subtelomeric Xq28. They detected a deletion involving the five probes spanning Xq26-Xq28. FISH with a cosmid probe (CLH 128) that defined Xq28 provided further evidence of a deletion in that region. Analysis with the X chromosome-specific cocktail probes spanning Xpter-qter showed hybridization signal all along the abnormal X, excluding the possibility of a cryptic translocation. However, sequential FISH with the X [alpha]-satellite probe DXZ1 and a probe for total human telomeres showed the presence of telomeres on both the normal and deleted X chromosomes. From the molecular and FISH analyses they interpret the deletion in this family as 46,X,del(X)(pter[r arrow]q26::qter). In light of previous phenotypic-karyotypic correlations, it can be deduced that this region contains a locus responsible for ovarian maintenance. 32 refs., 4 figs., 2 tabs.

Tharapel, A.T.; Simpson, J.L.; Martens, P.R.; Wilroy, R.S. Jr.; Llerena, J.C. Jr. (Univ. of Tennessee, Memphis (United States)); Anderson, K.P.; Schwartz, C.E. (Greenwood Genetics Center, SC (United States))

1993-03-01

369

Autism in Angelman Syndrome: An Exploration of Comorbidity  

ERIC Educational Resources Information Center

The aim was to explore the comorbidity between Angelman syndrome and autism spectrum disorders (ASDs). Identification of autism in children with Angelman syndrome presents a diagnostic challenge. In the present study, 16 children with Angelman syndrome, all with a 15q11-13 deletion, were examined for ASDs. Thirteen children with Angelman syndrome

Trillingsgaard, Anegen; Ostergaard, John R.

2004-01-01

370

Scoliosis in cat cry syndrome  

Microsoft Academic Search

Background  Cat cry syndrome is an autosomal disease accompanying abnormal deletion of chromosome 5 and occurs in only 1 of 50,000 neonates.\\u000a Scoliosis has been reported as a skeletal complication in cat cry syndrome. The characteristics and causes of scoliosis in\\u000a this rare syndrome are unknown. The purpose of this study was to present the characteristics of scoliosis in cat cry

Tsuneo Takebayashi; Hiroyuki Obata; Yasuhiko Minaki; Masatoshi Sekine; Kenshi Imoto; Kazutoshi Yokogushi; Toshihiko Yamashita

2006-01-01

371

Amniotic band syndrome.  

PubMed

Amniotic band syndrome is an uncommon congenital disorder without any genetic or hereditary disposition. It involves fetal entrapment in strands of amniotic tissue and causes an array of deletions and deformations. Primary treatment is plastic and reconstructive surgery after birth with in utero fetal surgery also coming in vogue. PMID:24426485

Shetty, Prathvi; Menezes, Leo Theobald; Tauro, Leo Francis; Diddigi, Kumar Arun

2013-10-01

372

Definition of the critical interval for Smith-Magenis syndrome  

Microsoft Academic Search

Smith-Magenis syndrome (SMS) comprises a complex physical and behavioral phenotype that is associated with an interstitial deletion of chromosome 17p11.2. The deletions observed in patients can range from <2 to >9 megabases of DNA and may include more than 100 genes. In order to determine the critical deletion interval responsible for the syndrome phenotype, we have examined several patients with

S. H. Elsea; S. M. Purandare; R. A. Adell; R. C. Juyal; J. G. Davis; B. Finucane; R. E. Magenis; P. I. Patel

1997-01-01

373

Two interstitial rearrangements (16q deletion and 17p duplication) in a child with MR/MCA  

PubMed Central

Key Clinical Meassage Patients with rare deletions in 16q12 and a duplication of 17p, both interstitial and de novo. Only seven cases have been described with these deletions and none of them presented other chromosomal abnormalities. The proband showed a complex phenotype with features found in patients with dup17p11.2 syndrome, deletions in 16q12. PMID:25548634

Sanchez-Jimeno, Carolina; Bustamante-Aragonés, Ana; Infantes-Barbero, Fernando; Rodriguez De Alba, Marta; Ramos, Carmen; Trujillo-Tiebas, María Jose; Lorda-Sánchez, Isabel

2014-01-01

374

Angelman Syndrome: Genetic Mechanisms and Relationship to Prader-Willi Syndrome.  

ERIC Educational Resources Information Center

Research points to two distinct regions within the Prader-Willi chromosome region: one for Prader Willi syndrome and one for Angelman syndrome. Genetic mechanisms in Angelman syndrome are complex, and at present, three mechanisms are recognized: maternal deletion, paternal uniparental disomy, and a nondeleted nondisomic form. (Author/JDD)

Smith, Arabella

1994-01-01

375

Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother  

E-print Network

Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal Unit, Bondy, France Running title: Duplication 16p11.2p12.2 in twins with autism Corresponding author recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual

Paris-Sud XI, Université de

376

A 13-year-old boy with a 7q36.1q36.3 deletion with additional findings.  

PubMed

Relatively little is known about 7q terminal deletion contiguous gene deletion syndrome. The deleted region includes more than 40 OMIM genes. We here report on a 13-year-old boy with7q terminal deletion syndrome, a 6.89-Mb sized deletion on 7q36.1q36.3, identified by oligonucleotide array comparative genomic hybridization (CGH). He showed microform holoprosencephaly with microcephaly, distinctive facial features, severe intellectual disabilities, behavior problems, seizures, short stature, penoscrotal transposition, and ulnar ray deficiency. To date, no case of penoscrotal transposition or ulnar ray deficiency has been reported in 7q terminal syndrome. The majority of our patient presentations were attributed to dosage expression of the SHH gene with contributions from deleted genes within 7q. © 2014 Wiley Periodicals, Inc. PMID:25257745

Hyohyeon, Cha; Lee, Cha Gon

2015-01-01

377

Evidence for a distinct region causing a cat-like cry in patients with 5p deletions  

SciTech Connect

The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth, which is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on four families in which patients with 5p deletions have only the characteristic cat-like cry, with normal to mildly delayed development. The precise locations of the deletions in each family were determined by FISH using lambda phage and cosmic clones. All of the deletion breakpoints map distal to a chromosomal region that is implicated with the facial features and severe mental and developmental delay in the cri-du-chat syndrome. DNA clones mapping in the chromosomal region associated with the cat-like cry feature will be useful diagnostic tools. They will allow for the distinction between 5p deletions that will result in the severe delay observed in most cri-du-chat syndrome patients and those deletions that result in the isolated cat-like cry feature, which is associated with a better prognosis. 19 refs., 5 figs., 1 tab.

Gersh, M.; Goodart, S.A.; Overhauser, J. [Thomas Jefferson Univ., Philadelphia, PA (United States)] [and others

1995-06-01

378

Functional Consequences of Mitochondrial DNA Deletions in Human Skin Fibroblasts  

PubMed Central

Deletions within the mitochondrial DNA (mtDNA) are thought to contribute to extrinsic skin aging. To study the translation of mtDNA deletions into functional and structural changes in the skin, we seeded human skin fibroblasts into collagen gels to generate dermal equivalents. These cells were either derived from Kearns-Sayre syndrome (KSS) patients, who constitutively carry large amounts of the UV-inducible mitochondrial common deletion, or normal human volunteers. We found that KSS fibroblasts, in comparison with normal human fibroblasts, contracted the gels faster and more strongly, an effect that was dependent on reactive oxygen species. Gene expression and Western blot analysis revealed significant upregulation of lysyl oxidase (LOX) in KSS fibroblasts. Treatment with the specific LOX inhibitor ?-aminopropionitrile decreased the contraction difference between KSS and normal human fibroblast equivalents. Also, addition of the antioxidant N-tert-butyl-?-phenylnitrone reduced the contraction difference by inhibiting collagen gel contraction in KSS fibroblasts, and both ?-aminopropionitrile and N-tert-butyl-?-phenylnitrone diminished LOX activity. These data suggest a causal relationship between mtDNA deletions, reactive oxygen species production, and increased LOX activity that leads to increased contraction of collagen gels. Accordingly, increased LOX expression was also observed in vivo in photoaged human and mouse skin. Therefore, mtDNA deletions in human fibroblasts may lead to functional and structural alterations of the skin. PMID:19661442

Majora, Marc; Wittkampf, Tanja; Schuermann, Bianca; Schneider, Maren; Franke, Susanne; Grether-Beck, Susanne; Wilichowski, Ekkehard; Bernerd, Françoise; Schroeder, Peter; Krutmann, Jean

2009-01-01

379

A candidate model for angelman syndrome in the mouse  

Microsoft Academic Search

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are well-recognized examples of imprinting in humans. They occur most\\u000a commonly with paternal and maternal 15ql 1-13 deletions, but also with maternal and paternal disomy. Both syndromes have also\\u000a occurred more rarely in association with smaller deletions seemingly causing abnormal imprinting. A putative mouse model of\\u000a PWS, occurring with maternal duplication (partial maternal

Bruce M. Cattanach; J. A. Barr; C. V. Beechey; J. Martin; J. Noebels; J. Jones

1997-01-01

380

Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly, mental retardation and leukencephalopathy.  

PubMed

Chromosome 18 abnormalities rank among the most common autosomal anomalies with 18q being the most frequently affected. A deletion of 18q has been attributed to microcephaly, mental retardation, short stature, facial dysmorphism, myelination disorders, limb and genitourinary malformations and congenital aural atresia. On the other hand, duplications of 18q have been associated with the phenotype of Edwards syndrome. Critical chromosomal regions for both phenotypes are contentious. In this report, we describe the first case of an 11-year old male with a combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 with phenotypic features of isolated 18q deletion syndrome and absence of phenotypic features characteristic of Edwards syndrome despite duplication of the suggested critical region. This report allows for reevaluation of proposed critical intervals for the phenotypes in deletion 18q syndrome and Edwards syndrome. PMID:23566840

Nguyen-Minh, Sylvie; Drossel, Katrin; Horn, Denise; Rost, Imma; Spors, Birgit; Kaindl, Angela M

2013-07-01

381

Deletion of chromosome 21 in a girl with congenital hypothyroidism and mild mental retardation  

SciTech Connect

We report on a girl with a large interstitial deletion of the long arm of chromosome 21 and with mild mental retardation, congenital hypothyroidism, and hyperopia. The deletion [del(21)(q11.1-q22.1)] extends molecularly from marker D21S215 to D21S213. The distal breakpoint is not clearly defined but is situated between markers D21S213 and IFNAR. This patient has the largest deletion of chromosome 21 known without having severe mental retardation or malformations. The deletion does not involve the {open_quotes}Down syndrome chromosome{close_quotes} region, the region of chromosome 21 which in trisomy causes most of the manifestations of Down syndrome. Apparently, the proximal part of the long arm of chromosome 21 does not include genes that are responsible for severe clinical effects in the event of either deletion or duplication, since several reported patients with either trisomy or deletion of this region have mild phenotypic abnormalities. Congenital hypothyroidism is much more common in Down syndrome than in the average population. Thus, the congenital hypothyroidism of the present patient might indicate that there is one or several genes on the proximal part of chromosome 21, which might be of importance for the thyroid function. 24 refs., 4 figs., 2 tabs.

Ahlbom, B.E.; Anneren, G. [Univ. Hospital, Uppsala (Sweden)] [Univ. Hospital, Uppsala (Sweden); Sidenvall, R. [Central Hospital of Hudiksvall (Sweden)] [Central Hospital of Hudiksvall (Sweden)

1996-08-23

382

Short stature in a mother and daughter with terminal deletion of Xp22.3  

SciTech Connect

Short stature in females is often caused by homozygosity for the terminal portion of Xp due to monosomy X or a deletion. We report on a mother and daughter with short stature as sole phenotypic abnormality and deletion of bands Xp22.32-p22.33 demonstrated by classic and molecular cytogenetic analysis. In both individuals, the deleted X chromosome was late replicating. Molecular analysis suggested that the deletion is terminal and the breakpoint was localized between the STS and DXS7470 loci in Xp22.32. Chromosome analysis is often done on females with short stature to exclude Ullrich-Turner syndrome. Small deletions, terminal or interstitial, are easily missed by conventional cytogenetic investigation; thus molecular analyses are useful to detect those cases. 8 refs., 3 figs.

Schwinger, E.; Kirschstein, M.; Konermann, T. [Institut fuer Humangenetik, Hamburg (Germany)] [and others] [Institut fuer Humangenetik, Hamburg (Germany); and others

1996-05-03

383