Note: This page contains sample records for the topic subtelomeric deletion syndrome from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: August 15, 2014.
1

TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions.  

PubMed

Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development. PMID:16773126

Rooms, Liesbeth; Reyniers, Edwin; Scheers, Stefaan; van Luijk, Rob; Wauters, Jan; Van Aerschot, Leen; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi; Mengus, Gabrielle; Davidson, Irwin; Courtens, Winnie; Kooy, R Frank

2006-10-01

2

Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation  

PubMed Central

Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.

Rio, M; Molinari, F; Heuertz, S; Ozilou, C; Gosset, P; Raoul, O; Cormier-Daire, V; Amiel, J; Lyonnet, S; Le Merrer, M; Turleau, C; de Blois, M-C; Prieur, M; Romana, S; Vekemans, M; Munnich, A; Colleaux, L

2002-01-01

3

Further phenotypic delineation of subtelomeric (terminal) 4q deletion with emphasis on intracranial and reproductive anatomy  

Microsoft Academic Search

OBJECTIVE: To describe selected morphological and developmental features associated with subtelomeric deletion at chromosome 4q. MATERIALS AND METHODS: A 21-year old female was brought for gynecologic evaluation of menorrhagia. High-resolution metaphase karyotype and subtelomere fluorescent in-situ hybridization (FISH) analysis were used for genotype determination. Pelvic anatomy was characterized via CT and laparoscopy; MR and CT were used for intracranial imaging.

Eric Scott Sills; MJ Burns; Laurinda D Parker; Lisa P Carroll; Lisa L Kephart; CS Dyer; Peter R Papenhausen; Jessica G Davis

2007-01-01

4

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

5

Subtelomeric deletions detected in patients with idiopathic mental retardation using multiplex ligation-dependent probe amplification (MLPA).  

PubMed

Subtelomeric rearrangements are responsible for 5% to 10% of cases of unexplained mental retardation. Despite their clinical relevance, methods to screen for these cytogenetically invisible abnormalities on a routine base are scarce. We screened patients with idiopathic mental retardation for subtelomeric aberrations using multiplex ligation-dependent probe amplification (MLPA). This recently developed technique is based on PCR amplification of ligated probes hybridized to chromosome ends. Currently, 41 telomeres can be screened in just two multiplex reactions. Four subtelomeric rearrangements (5.3%) were detected in a group of 75 patients with mild to severe mental retardation in combination with dysmorphic features and/or a familial history of mental retardation: two terminal 1p deletions, a terminal 1q deletion, and a terminal 3p deletion. Deletions could be verified by FISH and marker analysis. In one case the MLPA indicated a terminal 21q deletion due to a 3-bp deletion at the site of the probe, giving a false-positive rate of 1.3%. This study demonstrates that MLPA is a fast and reliable screening method, potentially suitable for use in routine diagnostics. PMID:14695528

Rooms, Liesbeth; Reyniers, Edwin; van Luijk, Rob; Scheers, Stefaan; Wauters, Jan; Ceulemans, Berten; Van Den Ende, Jenneke; Van Bever, Yolande; Kooy, R Frank

2004-01-01

6

Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome  

PubMed Central

We characterized at the molecular level the genomic rearrangements in 28 unrelated patients with 9q34.3 subtelomeric deletions. Four distinct categories were delineated: terminal deletions, interstitial deletions, derivative chromosomes and complex rearrangements; each results in haploinsufficiency of the EHMT1 gene and a characteristic phenotype. Interestingly, 25% of our patients had de novo interstitial deletions, 25% were found with derivative chromosomes and complex rearrangements and only 50% were bona fide terminal deletions. In contrast to genomic disorders that are often associated with recurrent rearrangements, breakpoints involving the 9q34.3 subtelomere region are highly variable. Molecular studies identified three regions of breakpoint grouping. Interspersed repetitive elements such as Alu, LINE, long-terminal repeats and simple tandem repeats are frequently observed at the breakpoints. Such repetitive elements may play an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes or assist in either DNA double-strand break repair or repair of single double-strand DNA ends generated by collapsed forks. Sequence analyses of the breakpoint junctions suggest that subtelomeric deletions can be stabilized by both homologous and nonhomologous recombination mechanisms, through a telomere-capture event, by de novo telomere synthesis, or multistep breakage-fusion-bridge cycles.

Yatsenko, Svetlana A.; Brundage, Ellen K.; Roney, Erin K.; Cheung, Sau Wai; Chinault, A. Craig; Lupski, James R.

2009-01-01

7

Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements  

PubMed Central

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.

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

2011-01-01

8

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

9

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

10

A de novo subtelomeric monosomy 11q (11q24.2-qter) and trisomy 20q (20q13.3-qter) in a girl with findings compatible with Jacobsen syndrome: case report and review.  

PubMed

We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome. PMID:17786114

Courtens, Winnie; Wauters, Jan; Wojciechowski, Marek; Reyniers, Edwin; Scheers, Stefan; van Luijk, Rob; Rooms, Liesbeth; Kooy, Frank; Wuyts, Wim

2007-10-01

11

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.

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

12

Clinical report of a pure subtelomeric 1qter deletion in a boy with mental retardation and multiple anomalies adds further evidence for a specific phenotype.  

PubMed

Deletions of the 1q telomere have been reported in several studies screening for subtelomeric rearrangements. However, an adequate clinical description is available from only a few patients. We provide a clinical description of a patient with a subtelomeric deletion of chromosome 1q, previously detected by us in a screening study. Comparison of the clinical presentation of our patient with rare cases reported previously provides further evidence for a specific phenotype of 1q patients, including mental retardation, growth retardation, sometimes with prenatal onset, progressive microcephaly, seizures, hand and foot abnormalities and a variety of midline defects, including corpus callosum, cardiac, genital and gastro-esophageal abnormalities. This clinical presentation is reminiscent of that of patients with larger, microscopically visible deletions of chromosome 1q (>3 Mb) characterized by growth and mental retardation, coarse faces with thin upper lip, epilepsy, and variable other anomalies. In addition, the breakpoint region was mapped to a 26 kb region within the RGS7 gene. Among the 17 known genes in the candidate region, are zinc-finger genes. Other members of this gene family have been implicated in different forms of mental retardation. PMID:15822126

van Bever, Yolande; Rooms, Liesbeth; Laridon, Annick; Reyniers, Edwin; van Luijk, Rob; Scheers, Stefaan; Wauters, Jan; Kooy, R Frank

2005-05-15

13

Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3)  

PubMed Central

Summary In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%–10% of cases.

Holinski-Feder, Elke; Reyniers, Edwin; Uhrig, Sabine; Golla, Astrid; Wauters, Jan; Kroisel, Peter; Bossuyt, Paul; Rost, Imma; Jedele, Kerry; Zierler, Hannelore; Schwab, Sieglinde; Wildenauer, Dieter; Speicher, Michael R.; Willems, Patrick J.; Meitinger, Thomas; Kooy, R. Frank

2000-01-01

14

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3).  

PubMed

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases. PMID:10631133

Holinski-Feder, E; Reyniers, E; Uhrig, S; Golla, A; Wauters, J; Kroisel, P; Bossuyt, P; Rost, I; Jedele, K; Zierler, H; Schwab, S; Wildenauer, D; Speicher, M R; Willems, P J; Meitinger, T; Kooy, R F

2000-01-01

15

Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA)  

PubMed Central

Background: Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated. Objective: To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA). Methods: 210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the SALSA P036 human telomere test kit, was used. Results: A subtelomeric aberration was identified in 14 patients (6.7%) (10 deletions and four duplications). Five deletions were de novo; four were inherited from phenotypically normal parents, suggesting that these were polymorphisms. For one deletion, DNA samples of the parents were not available. Two de novo submicroscopic duplications were detected (dup 5qter, dup 12pter), while the other duplications (dup 18qter and dup 22qter) were inherited from phenotypically similarly affected parents. All clinically relevant aberrations (de novo or inherited from similarly affected parents) occurred in patients with a clinical score of ?3 using an established checklist for subtelomeric rearrangements. Testing of patients with a clinical score of ?3 increased the diagnostic yield twofold to 12.4%. Abnormalities with clinical relevance occurred in 6.3%, 5.1%, and 1.7% of mildly, moderately, and severely retarded patients, respectively, indicating that testing for subtelomeric aberrations among mildly retarded individuals is necessary. Conclusions: The value of MLPA is confirmed. Subtelomeric screening can be offered to all mentally retarded patients, although clinical preselection increases the percentage of chromosomal aberrations detected. Duplications may be a more common cause of mental retardation than has been appreciated.

Koolen, D; Nillesen, W; Versteeg, M; Merkx, G; Knoers, N; Kets, M; Vermeer, S; van Ravenswaaij, C M A; de Kovel, C G; Brunner, H; Smeets, D; de Vries, B B A; Sistermans, E

2004-01-01

16

Deletion 22q13.3 syndrome  

PubMed Central

The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy). Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements. Individuals with deletion 22q13 should have routine examinations by the primary care physician as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. No apparent life-threatening organic abnormalities accompany the diagnosis of deletion 22q13.

Phelan, Mary C

2008-01-01

17

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 ...

18

Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA)  

Microsoft Academic Search

BACKGROUND: Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated. OBJECTIVE: To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA). METHODS: 210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the

D. A. Koolen; W. M. Nillesen; M. H. Versteeg; G. F. M. Merkx; N. V. A. M. Knoers; M. Kets; S. Vermeer; C. M. A. van Ravenswaaij-Arts; C. G. F. de Kovel; H. G. Brunner; D. F. C. M. Smeets; L. B. A. de Vries; E. A. Sistermans

2004-01-01

19

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 ...

20

Genetics Home Reference: 2q37 deletion syndrome  

MedlinePLUS

... cases have been reported worldwide. What are the genetic changes related to 2q37 deletion syndrome? 2q37 deletion ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

21

Genetics Home Reference: 16p11.2 deletion syndrome  

MedlinePLUS

... deletion may never be detected. What are the genetic changes related to 16p11.2 deletion syndrome? People ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

22

Clinical phenotype and molecular characterization of 6q terminal deletion syndrome: Five new cases.  

PubMed

Mental retardation, facial dysmorphisms, seizures, and brain abnormalities are features of 6q terminal deletions. We have ascertained five patients with 6q subtelomere deletions (four de novo, one as a result of an unbalanced translocation) and determined the size of the deletion ranging from 3 to 13 Mb. Our patients showed a recognizable phenotype including mental retardation, characteristic facial appearance, and a distinctive clinico-neuroradiological picture. Focal epilepsy with consistent electroencephalographic features and with certain brain anomalies on neuroimaging studies should suggest 6q terminal deletion. The awareness of the distinctive clinical picture will help in the diagnosis of this chromosomal abnormality. PMID:16906558

Striano, Pasquale; Malacarne, Michela; Cavani, Simona; Pierluigi, Mauro; Rinaldi, Rosanna; Cavaliere, Maria Luigia; Rinaldi, Maria Michela; De Bernardo, Carmelilia; Coppola, Antonietta; Pintaudi, Maria; Gaggero, Roberto; Grammatico, Paola; Striano, Salvatore; Dallapiccola, Bruno; Zara, Federico; Faravelli, Francesca

2006-09-15

23

Genetics Home Reference: 22q11.2 deletion syndrome  

MedlinePLUS

... other disorders with overlapping features. What are the genetic changes related to 22q11.2 deletion syndrome? Most ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

24

Two novel deletions in hypotonia-cystinuria syndrome.  

PubMed

Hypotonia-cystinuria syndrome (HCS) is an autosomal recessive disorder caused by combined deletions of SLC3A1 and PREPL. Clinical features include cystinuria, neonatal hypotonia with spontaneous improvement, poor feeding in neonates, hyperphagia in childhood, growth hormone deficiency, and variable cognitive problems. Only 14 families with 6 different deletions have been reported. Patients are often initially misdiagnosed, while correct diagnosis enables therapeutic interventions. We report two novel deletions, further characterizing the clinical and molecular genetics spectrum of HCS. PMID:22796000

Régal, Luc; Aydin, Halil Ibrahim; Dieltjens, Anne-Marie; Van Esch, Hilde; Francois, Inge; Okur, Ilyas; Zeybek, Cengiz; Meulemans, Sandra; Van Mol, Christine; Van Bruwaene, Lore; Then, Siao-Hann; Jaeken, Jaak; Creemers, John

2012-11-01

25

The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)  

PubMed Central

The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Over 600 cases of 22q13.3 deletion syndrome have been documented. Most are terminal deletions of ?100 kb to >9 Mb, resulting from simple deletions, ring chromosomes, and unbalanced translocations. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. Two mouse knockout models and cell culture experiments show that SHANK3 is involved in the structure and function of synapses and support the hypothesis that the majority of 22q13.3 deletion syndrome neurological defects are due to haploinsufficiency of SHANK3, although other genes in the region may also play a role in the syndrome. The molecular connection to ASD suggests that potential future treatments may involve modulation of metabotropic glutamate receptors.

Phelan, K.; McDermid, H.E.

2012-01-01

26

Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage-fusion-bridge for telomere stabilization.  

PubMed

Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion syndrome, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion-duplication or duplication-triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in Caenorhabditis elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication. PMID:22890305

Yatsenko, Svetlana A; Hixson, Patricia; Roney, Erin K; Scott, Daryl A; Schaaf, Christian P; Ng, Yu-tze; Palmer, Robbin; Fisher, Richard B; Patel, Ankita; Cheung, Sau Wai; Lupski, James R

2012-12-01

27

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.

Ozsu, Elif; Yesiltepe Mutlu, Gul; Bute Yuksel, Aysegul; Hatun, Sukru

2014-01-01

28

Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay  

PubMed Central

Background Subtelomeric regions are gene rich and deletions in these chromosomal segments have been demonstrated to account for approximately 2.5% of patients displaying mental retardation with or without association of dysmorphic features. However, cases that report de novo terminal deletions on chromosome arm 15q are rare. Methods In this study we present the first example of a detailed molecular genetic mapping of a de novo deletion in involving 15q26.2-qter, caused by the formation of a dicentric chromosome 15, using metaphase FISH and tiling resolution (32 k) genome-wide array-based comparative genomic hybridization (CGH). Results After an initial characterization of the dicentric chromosome by metaphase FISH, array CGH analysis mapped the terminal deletion to encompass a 6.48 megabase (Mb) region, ranging from 93.86–100.34 Mb on chromosome 15. Conclusion In conclusion, we present an additional case to the growing family of reported cases with 15q26-deletion, thoroughly characterized at the molecular cytogenetic level. In the deleted regions, four candidate genes responsible for the phenotype of the patient could be delineated: IGFR1, MEF2A, CHSY1, and TM2D3. Further characterization of additional patients harboring similar 15q-aberrations might hopefully in the future lead to the description of a clear cut clinically recognizable syndrome.

Davidsson, Josef; Collin, Anna; Bjorkhem, Gudrun; Soller, Maria

2008-01-01

29

Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.  

PubMed Central

We have previously described a fluorescence in situ hybridisation (FISH) assay for the simultaneous analysis of all human subtelomeric regions using a single microscope slide. Here we report the use of this multiprobe FISH assay in the study of a patient whose karyotype was reported by G banding analysis as 46,XX,del(18)(p11.2). Although the proband had some features suggestive of a chromosomal abnormality, relatively few of the specific features of del(18p) were present. She was a 37 year old female with mild distal spinal muscular atrophy (SMA), arthritis of the hands, an abnormal chest shape (pectus excavatum), and an unusual skin condition (keratosis pilaris). Reverse chromosome painting with degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR) amplified del(18p) chromosomes as a probe confirmed the abnormality as del(18p), with no evidence of any other chromosome involvement. Subsequently, the multiprobe FISH assay confirmed deletion of 18p subtelomeric sequence. However, the assay also showed that sequences corresponding to the 2p subtelomeric probe were present on the tip of the shortened 18p. The patient is therefore monosomic for 18p11.2-pter and trisomic for 2p25-pter, and the revised karyotype is 46,XX,der(18)t(2;18)(p25; p11.2). We believe that a proportion of all cases reported as telomeric deletions may be cryptic translocations involving other chromosome subtelomeric regions. Further studies such as this are necessary to define accurately the clinical characteristics associated with pure monosomy in chromosomal deletion syndromes. Images

Horsley, S W; Knight, S J; Nixon, J; Huson, S; Fitchett, M; Boone, R A; Hilton-Jones, D; Flint, J; Kearney, L

1998-01-01

30

Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage - fusion - bridge for telomere stabilization  

PubMed Central

Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion-duplication or duplication-triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in C elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication.

Yatsenko, Svetlana A.; Hixson, Patricia; Roney, Erin K.; Scott, Daryl A.; Schaaf, Christian P.; Ng, Yu-tze; Palmer, Robbin; Fisher, Richard B.; Patel, Ankita; Cheung, Sau Wai; Lupski, James R.

2012-01-01

31

Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter  

PubMed Central

Background Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. Methods We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. Results We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Conclusion Subtelomeric screening is a useful adjunct to conventional cytogenetic analyses, and should be considered in mentally retarded subjects with dysmorphic features and unknown cause.

Sogaard, Marie; Tumer, Zeynep; Hjalgrim, Helle; Hahnemann, Johanne; Friis, Birgitte; Ledaal, Paal; Pedersen, Vibeke Faurholt; Baekgaard, Peter; Tommerup, Niels; Cingoz, Sultan; Duno, Morten; Brondum-Nielsen, Karen

2005-01-01

32

Large Contiguous Gene Deletions in Sj?gren-Larsson Syndrome  

PubMed Central

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

Engelstad, Holly; Carney, Gael; S'Aulis, Dana; Rise, Janae; Sanger, Warren G.; Rudd, M. Katharine; Richard, Gabriele; Carr, Christopher W.; Abdul-Rahman, Omar A.; Rizzo, William B.

2011-01-01

33

Large contiguous gene deletions in Sjögren-Larsson syndrome.  

PubMed

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis. PMID:21684788

Engelstad, Holly; Carney, Gael; S'aulis, Dana; Rise, Janae; Sanger, Warren G; Rudd, M Katharine; Richard, Gabriele; Carr, Christopher W; Abdul-Rahman, Omar A; Rizzo, William B

2011-11-01

34

22q11.2 Deletion Syndrome: Genetics, Neuroanatomy and Cognitive\\/Behavioral Features Keywords  

Microsoft Academic Search

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.

Kevin M. Antshel; Wendy R. Kates; Nancy Roizen; Wanda Fremont; Robert J. Shprintzen

2005-01-01

35

Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation  

PubMed Central

Background Subtelomeric imbalance is widely accepted as related to developmental delay/mental retardation (DD/MR). Fine mapping of aberrations in gene-enriched subtelomeric regions provides essential clues for localizing critical regions, and provides a strategy for identifying new candidate genes. To date, no large-scale study has been conducted on subtelomeric aberrations in DD/MR patients in mainland China. Methods This study included 451 Chinese children with moderate to severe clinically unexplained DD/MR. The subtelomere-MLPA (multiplex ligation dependent probe amplification) and Affymetrix human SNP array 6.0 were used to determine the subtelomeric copy number variations. The exact size and the breakpoint of each identified aberration were well defined. Results The submicroscopic subtelomeric aberrations were identified in 23 patients, with a detection rate of 5.1%. 16 patients had simple deletions, 2 had simple duplications and 5 with both deletions and duplications. The deletions involved 14 different subtelomeric regions (1p, 2p, 4p, 6p, 7p, 7q, 8p, 9p, 10p, 11q, 14q, 15q, 16p and 22q), and duplications involved 7 subtelomeric regions (3q, 4p, 6q, 7p, 8p, 12p and 22q). Of all the subtelomeric aberrations found in Chinese subjects, the most common was 4p16.3 deletion. The sizes of the deletions varied from 0.6 Mb to 12 Mb, with 5-143 genes inside. Duplicated regions were 0.26 Mb to 11 Mb, with 6-202 genes inside. In this study, four deleted subtelomeric regions and one duplicated region were smaller than any other previously reported, specifically the deletions in 11q25, 8p23.3, 7q36.3, 14q32.33, and the duplication in 22q13. Candidate genes inside each region were proposed. Conclusions Submicroscopic subtelomeric aberrations were detected in 5.1% of Chinese children with clinically unexplained DD/MR. Four deleted subtelomeric regions and one duplicated region found in this study were smaller than any previously reported, which will be helpful for further defining the candidate dosage sensitive gene associated with DD/MR.

2010-01-01

36

Xp22. 3 deletions in isolated familial Kallmann's syndrome  

SciTech Connect

Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. (Institut Pasteur, Paris (France)); Young, J.; Pholsena, M.; Schaison, G. (Centre Hospitalier de Bicetre, Le Kremlin-Bicetre (France)); Kirk, J.; Bouloux, P. (Royal Free Hospital, London (United Kingdom))

1993-04-01

37

Diverse chromosome breakage mechanisms underlie subtelomeric rearrangements, a common cause of mental retardation.  

PubMed

Subtelomeric rearrangements are an important cause of both isolated and familial idiopathic mental retardation. A variety of different rearrangements such as pure truncations, unbalanced translocations, interstitial deletions, and inverted duplications have been detected throughout various screening studies. The cause of these aberrations is poorly understood as only few of the breakpoints have been determined and studied. We molecularly characterized the breakpoints of three rearrangements including a 1p subtelomeric deletion, a 1q subtelomeric deletion, and an unbalanced translocation between chromosomes 11q and 20q; we propose that diverse chromosome breakage mechanisms underlie subtelomeric rearrangements. The breakpoint sequences suggest that unusual non-B-DNA structures including triplex, tetraplex, and hairpin structures may be involved. In addition, we saw that the seemingly pure truncations of chromosomes 1p and 1q were in fact more complex rearrangements as highly repetitive sequences were joined to the chromosome end at the site of breakage. PMID:16991117

Rooms, Liesbeth; Reyniers, Edwin; Kooy, R Frank

2007-02-01

38

Surgical considerations in 22Q11.2 deletion syndrome.  

PubMed

The 22q11.2 deletion syndrome (22q11DS) may be associated with several palatal abnormalities, including overt cleft palate, submucosal cleft palate, palatopharyngeal disproportion, and velar hypotonia. The syndrome is the genetic disorder most commonly associated with velopharyngeal dysfunction (VPD). The complex causes of VPD in affected patients combine with the complexity of associated medical disorders to render surgical management of the velopharynx particularly challenging. Optimization of surgical outcomes requires precision in diagnosis, surgical management, and multidisciplinary care. This article provides an overview of 22q11DS and provides a review of the assessment and surgical management of VPD in affected individuals. PMID:24607194

Kirschner, Richard E; Baylis, Adriane L

2014-04-01

39

Xp22. 3 deletions in isolated familial Kallmann's syndrome  

Microsoft Academic Search

Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been

J. P. Hardelin; J. Levilliers; R. Legouis; C. Petit; J. Young; M. Pholsena; G. Schaison; J. Kirk; P. Bouloux

1993-01-01

40

Supporting Children with Genetic Syndromes in the Classroom: The Example of 22q Deletion Syndrome  

ERIC Educational Resources Information Center

An increasing number of children are likely to have a known genetic cause for their special educational needs. One such genetic condition is 22q11.2 deletion syndrome (22qDS), a genetic syndrome associated with early speech and language difficulties, global and specific cognitive impairments, difficulties with attention and difficulties with…

Reilly, Colin; Stedman, Lindsey

2013-01-01

41

Developmental Trajectories in Syndromes with Intellectual Disability, with a Focus on Wolf-Hirschhorn and Its Cognitive-Behavioral Profile  

ERIC Educational Resources Information Center

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn…

Fisch, Gene S.; Carpenter, Nancy; Howard-Peebles, Patricia N.; Holden, Jeanette J. A.; Tarleton, Jack; Simensen, Richard; Battaglia, Agatino

2012-01-01

42

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.

2014-01-01

43

Combination of WAGR and Potocki–Shaffer contiguous deletion syndromes in a patient with an 11p11.2–p14 deletion  

Microsoft Academic Search

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki–Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be

Dominique Brémond-Gignac; John A Crolla; Henri Copin; Agnès Guichet; Dominique Bonneau; Laurence Taine; Didier Lacombe; Clarisse Baumann; Brigitte Benzacken; Alain Verloes

2005-01-01

44

Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11  

Microsoft Academic Search

The conotruncal anomaly face syndrome was described in a Japanese publication in 1976 and comprises dysmorphic facial appearance and outflow tract defects of the heart. The authors subsequently noted similarities to Shprintzen syndrome and DiGeorge syndrome. Chromosome analysis in five cases did not show a deletion at high resolution, but fluorescent in situ hybridisation using probe DO832 showed a deletion

J Burn; A Takao; D Wilson; I Cross; K Momma; R Wadey; P Scambler; J Goodship

1993-01-01

45

Hematological abnormalities and 22q11.2 deletion syndrome  

PubMed Central

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.

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

2011-01-01

46

Mathematical Learning Disabilities in Children with 22q11.2 Deletion Syndrome: A Review  

ERIC Educational Resources Information Center

Mathematical learning disabilities (MLD) occur frequently in children with specific genetic disorders, like Turner syndrome, fragile X syndrome and neurofibromatosis. This review focuses on MLD in children with chromosome 22q11.2 deletion syndrome (22q11DS). This syndrome is the most common known microdeletion syndrome with a prevalence of at…

De Smedt, Bert; Swillen, Ann; Verschaffel, Lieven; Ghesquiere, Pol

2009-01-01

47

Human subtelomeric duplicon structure and organization  

PubMed Central

Background Human subtelomeric segmental duplications ('subtelomeric repeats') comprise about 25% of the most distal 500 kb and 80% of the most distal 100 kb in human DNA. A systematic analysis of the duplication substructure of human subtelomeric regions was done in order to develop a detailed understanding of subtelomeric sequence organization and a nucleotide sequence-level characterization of subtelomeric duplicon families. Results The extent of nucleotide sequence divergence within subtelomeric duplicon families varies considerably, as does the organization of duplicon blocks at subtelomere alleles. Subtelomeric internal (TTAGGG)n-like tracts occur at duplicon boundaries, suggesting their involvement in the generation of the complex sequence organization. Most duplicons have copies at both subtelomere and non-subtelomere locations, but a class of duplicon blocks is identified that are subtelomere-specific. In addition, a group of six subterminal duplicon families are identified that, together with six single-copy telomere-adjacent segments, include all of the (TTAGGG)n-adjacent sequence identified so far in the human genome. Conclusion Identification of a class of duplicon blocks that is subtelomere-specific will facilitate high-resolution analysis of subtelomere repeat copy number variation as well as studies involving somatic subtelomere rearrangements. The significant levels of nucleotide sequence divergence within many duplicon families as well as the differential organization of duplicon blocks on subtelomere alleles may provide opportunities for allele-specific subtelomere marker development; this is especially true for subterminal regions, where divergence and organizational differences are the greatest. These subterminal sequence families comprise the immediate cis-elements for (TTAGGG)n tracts, and are prime candidates for subtelomeric sequences regulating telomere-specific (TTAGGG)n tract length in humans.

Ambrosini, Anthony; Paul, Sheila; Hu, Sufen; Riethman, Harold

2007-01-01

48

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

49

Autism, ADHD, Mental Retardation and Behavior Problems in 100 Individuals with 22q11 Deletion Syndrome  

ERIC Educational Resources Information Center

This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens. Autism spectrum disorders (ASDs) and/or attention…

Niklasson, Lena; Rasmussen, Peder; Oskarsdottir, Solveig; Gillberg, Christopher

2009-01-01

50

Contiguous Gene Syndromes Due to Deletions in the Distal Short Arm of the Human X Chromosome  

Microsoft Academic Search

Mendelian inherited disorders due 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 combinations in 27 patients with interstitial and terminal deletions involving the distal short arm of the X chromosome. The

A. Ballabio; B. Bardoni; R. Carrozzo; G. Andria; D. Bick; L. Campbell; B. Hamel; M. A. Ferguson-Smith; G. Gimelli; M. Fraccaro; P. Maraschio; O. Zuffardi; S. Guioli; G. Camerino

1989-01-01

51

Classical Noonan syndrome is not associated with deletions of 22q11  

SciTech Connect

Deletions of 22q11 cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22q11 deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22q11 deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22q11 deletion. A 2-month-old infant with several findings suggestive of NS did have a 22q11 deletion, suggesting that a small number of 22q11 deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. 10 refs., 1 fig.

Robin, N.H.; Sellinger, B.; McDonald-McGinn, D. [Children`s Hospital of Philadelphia, PA (United States)] [and others

1995-03-13

52

Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes  

Microsoft Academic Search

Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion

Bekim Sadikovic; Jing Wang; Ayman El-Hattab; Megan Landsverk; Ganka Douglas; Ellen K. Brundage; William J. Craigen; Eric S. Schmitt; Lee-Jun C. Wong; Roland G. Roberts

2010-01-01

53

Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer  

Microsoft Academic Search

Hemizygous deletions are common molecular abnormalities in cancer. In some cases, these deletions highlight chromosomal loci containing tumor suppressor genes that undergo homozygous inactivation. In other cases, hemizygous deletions cause disease by allelic insufficiency for one or more genes. As the intact allele has no identifiable lesions, functional approaches are critical for the identification of pathogenic genes within large deletions.

B L Ebert

2009-01-01

54

[TSC2/PKD1 contiguous gene deletion syndrome].  

PubMed

The TSC2 gene responsible for Tuberous Sclerosis, is located in chromosome 16p 13.3, adjacent to the gene for autosomal dominant polycystic kidney disease. A large deletion can involve both genes, causing the so-called TSC2/PKD1 contiguous gene syndrome (MIM#600273). It is characterized by congenital renal cysts, or their early onset in patients with tuberous sclerosis, and implies a worst prognosis in renal disease. We report the case of a five year-old boy with tuberous sclerosis, who presented with multiple large bilateral renal cysts in the neonatal period. A genetic confirmation study was later performed using the multiple ligation probe amplification (MLPA) technique. PMID:23402778

Llamas Velasco, S; Camacho Salas, A; Vidales Moreno, C; Ceballos Rodríguez, R M; Murcia García, F J; Simón de la Heras, R

2013-07-01

55

Growth hormone deficiency in 18q deletion syndrome  

SciTech Connect

The 18q- syndrome is one of the most common chromosomal deletion syndromes. Clinical characteristics are variable but may include: hypotonia, cleft palate, mental retardation and hearing impairment. Growth failure (GF) (<3% weight/height) is present in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 15 patients with 18q- syndrome. Of these 15 patients, 10 have growth failure (<3% weight/height); of the remaining 5, 3 had normal growth parameters and 2 had growth along the 5%. Twelve patients failed to produce adequate GH following standard stimulation testing. Of these 12 patients with inadequate GH production, 2 had normal growth (above 3%). Of the 15, only 1 has normal GH production and normal growth parameters. Bone age was obtained on 1 patient with both GH deficiency and GF, and revealed significant delays. GH levels in response to GH releasing factor were normal in 3 out of 4 patients. MRI studies of GH-deficient patients indicated normal midline structures. Myelination in the few studied GH-deficient patients appeared delayed. The gene for myelin basic protein (MBP) is known to be located on the terminal portion of the long arm of chromosome 18. Neither the gene for GH, GH releasing factor nor GH releasing factor receptor is on chromosome 18. These genes are located on chromosomes 17, chromosome 20 and chromosome 7, respectively. Findings to date suggest that GH deficiency is common in individuals with 18q- syndrome. The etiology of this finding is unknown. We postulate that a gene(s) on chromosome 18q is involved in GH expression.

Ghidoni, P.D.; Cody, J.; Danney, J. [Univ. of Texas Health Science Center, San Antonio, TX (United States)] [and others

1994-09-01

56

Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome)  

Microsoft Academic Search

Objectives22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome (VCFS) or DiGeorge Syndrome, is a genetic disorder due to a micro deletion on chromosome 22q11.2. VCFS is associated with abnormalities in brain structure and with an increased risk of psychiatric disorders, particularly schizophrenia. The aim of this review was to statistically summarize the structural imaging literature on VCFS which due

Giles M. Tan; Danilo Arnone; Andrew M. McIntosh; Klaus P. Ebmeier

2009-01-01

57

Prenatal diagnosis of 22q11.2 deletion syndrome in twin pregnancy: a case report.  

PubMed

Chromosome 22q11.2 deletion syndrome is a common genetic disorder, also known as DiGeorge syndrome. It occurs in approximately 1:4,000 births, and the incidence is increasing due to affected parents bearing their own affected children. We report the prenatal diagnosis of 22q11.2 deletion syndrome by fluorescence in situ hybridization in twin fetuses having tetralogy of Fallot with absent pulmonary valve. PMID:22997003

Gul, Ahmet; Gungorduk, Kemal; Turan, Isil; Yildirim, Gokhan; Gedikbasi, Ali; Ozdemir, Aykut

2013-01-01

58

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated  

PubMed Central

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

Corsten-Janssen, N.; Saitta, S.C.; Hoefsloot, L.H.; McDonald-McGinn, D.M.; Driscoll, D.A.; Derks, R.; Dickinson, K.A.; Kerstjens-Frederikse, W.S.; Emanuel, B.S.; Zackai, E.H.; van Ravenswaaij-Arts, C.M.A.

2013-01-01

59

Parental origin of de novo chromosome 9 deletions in del(9p) syndrome  

SciTech Connect

Parental origin of de novo deletions in the short arm of chromosome 9 in patients with a clinical diagnosis of del(9p) syndrome was assessed in 13 patients using polymerase chain reaction (PCR) analysis of highly polymorphic dinucleotide repeat microsatellite markers located in the putative deleted region. The deletion was found to be of paternal origin in 9 cases and of maternal origin in the remaining 4 cases, suggesting that the molecular event resulting in the deletion occurs in both male and female gametogenesis and that genomic imprinting does not appear to play a role in the pathogenesis of del(9p) syndrome. 22 refs., 1 fig.

Micale, M.A.; Haren, J.M.; Conroy, J.M. [Case Western University School of Medicine, Clevelend, OH (United States)

1995-05-22

60

Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions  

SciTech Connect

Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.

Lindsay, E.A.; Goldberg, R.; Jurecic, V. [and others

1995-07-03

61

22q13.3 Deletion Syndrome: Clinical and Molecular Analysis Using Array CGH  

PubMed Central

The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype–phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype–phenotype correlations.

Dhar, S.U.; del Gaudio, D.; German, J.R.; Peters, S.U.; Ou, Z.; Bader, P.I.; Berg, J.S.; Blazo, M.; Brown, C.W.; Graham, B.H.; Grebe, T.A.; Lalani, S.; Irons, M.; Sparagana, S.; Williams, M.; Phillips, J.A.; Beaudet, A.L.; Stankiewicz, P.; Patel, A.; Cheung, S.W.; Sahoo, T.

2011-01-01

62

Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?  

PubMed

We report a full-term male infant born to nonconsanguinous parents who had clinical features of Goldenhar syndrome and cri du chat syndrome. At birth, the infant was noted to have dysmorphic features with bilateral preauricular tags, rotated ears, bilateral epicanthic folds, a left epibulbar lipodermoid, and an accessory left nipple. After he was assessed for feeding difficulty and tachypnea, he was found to have esophageal atresia with tracheoesophageal fistula. In addition, he had a high-pitched, cat-like cry, characteristic of cri-du-chat syndrome. He also failed a hearing test. Chromosomal analysis and fluorescence in situ hybridisation studies showed an unbalanced karyotype with a terminal deletion of the segment p14 on the short arm of chromosome 5, which is consistent with the cri-du-chat locus. The association of Goldenhar syndrome and cri-du-chat syndrome in this patient suggests that the chromosome 5p14 locus may harbor a gene implicated with Goldenhar syndrome. PMID:12825068

Choong, Yee Fong; Watts, Patrick; Little, Elizabeth; Beck, Lyn

2003-06-01

63

Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics.  

PubMed

Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients. PMID:16451137

Rooms, L; Reyniers, E; Wuyts, W; Storm, K; van Luijk, R; Scheers, S; Wauters, J; van den Ende, J; Biervliet, M; Eyskens, F; van Goethem, G; Laridon, A; Ceulemans, B; Courtens, W; Kooy, R F

2006-01-01

64

Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions  

Microsoft Academic Search

Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group

Elizabeth A. Lindsay; Rosalie Goldberg; Vesna Jurecic; Bernice Morrow; Christine Carlson; Raju S. Kucherlapati; Robert J. Shprintzen; Antonio Baldini

1995-01-01

65

Language Skills in 5-8-Year-Old Children with 22q11 Deletion Syndrome  

ERIC Educational Resources Information Center

Background: Language impairment and delayed language onset have been described, although not investigated in detail, in children with 22q11 deletion syndrome. Aims: To investigate different areas of language: the ability to retell a narrative, phonology, syntax and receptive vocabulary in a group of 5-8-year-old children with 22q11 deletion

Persson, Christina; Niklasson, Lena; Oskarsdottir, Solveig; Johansson, Susanne; Jonsson, Radi; Soderpalm, Ewa

2006-01-01

66

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

67

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

68

Natural Variation in a Subtelomeric Region of Arabidopsis: Implications for the Genomic Dynamics of a Chromosome End  

PubMed Central

We investigated genome dynamics at a chromosome end in the model plant Arabidopsis thaliana through a study of natural variation in 35 wild accessions. We focused on the single-copy subtelomeric region of chromosome 1 north (?3.5 kb), which represents the relatively simple organization of subtelomeric regions in this species. PCR fragment-length variation across the subtelomeric region indicated that the 1.4-kb distal region showed elevated structural variation relative to the centromere-proximal region. Examination of nucleotide sequences from this 1.4-kb region revealed diverse DNA rearrangements, including an inversion, several deletions, and an insertion of a retrotransposon LTR. The structures at the deletion and inversion breakpoints are characteristic of simple deletion-associated nonhomologous end-joining (NHEJ) events. There was strong linkage disequilibrium between the distal subtelomeric region and the proximal telomere, which contains degenerate and variant telomeric repeats. Variation in the proximal telomere was characterized by the expansion and deletion of blocks of repeats. Our sample of accessions documented two independent chromosome-healing events associated with terminal deletions of the subtelomeric region as well as the capture of a scrambled mitochondrial DNA segment in the proximal telomeric array. This natural variation study highlights the variety of genomic events that drive the fluidity of chromosome termini.

Kuo, Hui-Fen; Olsen, Kenneth M.; Richards, Eric J.

2006-01-01

69

Refinement of the Smith–Magenis syndrome critical region to ?950 kb and assessment of 17p11.2 deletions. Are all deletions created equally?  

Microsoft Academic Search

Smith–Magenis syndrome (SMS) is a multiple congenital anomalies\\/mental retardation syndrome associated with an interstitial deletion of chromosome 17p11.2. SMS is thought to be a contiguous gene syndrome caused by haploinsufficiency of one or more genes in the associated deletion region. To date, no gene has been reported to contribute to the characteristics seen in the SMS phenotype. To expedite the

Christopher N Vlangos; Dwight K. C Yim; Sarah H Elsea

2003-01-01

70

Craniosynostosis and radial ray defect: a rare presentation of 22q11.2 deletion syndrome.  

PubMed

A newborn with bilateral coronal craniosynostosis, hypoplastic thumbs, imperforate anus, and prenatal growth restriction was evaluated and given the clinical diagnosis of Baller-Gerold syndrome (BGS). While confirmatory testing of RECQL4 was pending, the infant developed unexplained hypocalcemia, prompting testing for a 22q11.2 deletion. Subsequently, the infant was found to have a 22q11.2 deletion, and was negative for an RECQL4 mutation. We therefore conclude that 22q11.2 deletion syndrome can present with findings resembling the BGS phenotype. PMID:23813949

Rojnueangnit, Kitiwan; Robin, Nathaniel H

2013-08-01

71

POLYMICROGYRIA IN CHROMOSOME 22q11 DELETION SYNDROME  

Microsoft Academic Search

Central nervous system (CNS) dysfunction is a cardinal feature in 22q11 deletion. The underlying CNS abnormalities remain, however, unknown. We report unilateral hemispheric polymicrogyria in a child with 22q11 deletion presenting with hemiplegia and cognitive and behavioural disorders. This observation widens the spectrum of brain malformations associated with this genetic defect. It further suggests a relationship between the 22q11 deletion

Sophie Ghariani; Karin Dahan; Christine Saint-Martin; Hazim Kadhim; Françoise Morsomme; Stéphane Moniotte; Christine Verellen-Dumoulin; Guillaume Sébire

2002-01-01

72

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

73

Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review.  

PubMed

Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition. PMID:23938213

Tutlewska, Katarzyna; Lubinski, Jan; Kurzawski, Grzegorz

2013-01-01

74

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

75

4q34.1-q35.2 deletion in a boy with phenotype resembling 22q11.2 deletion syndrome.  

PubMed

Small terminal or interstitial deletions involving bands 4q34 and 4q35 have been described in several patients with a relatively mild phenotype such as mild to moderate intellectual disability and minor dysmorphic features. We present a boy born from unrelated parents with a de novo 4q34.1-q35.2 deletion and clinical features resembling 22q11.2 deletion syndrome. To the best of our knowledge, this is the first reported patient with 4q34-q35 deletion and phenotype resembling 22q11.2 deletion syndrome without fifth finger anomalies as a specific feature of 4q- syndrome. G-banding karyotyping disclosed the deletion, which was further delineated by microarray comparative genomic hybridization. Fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses did not reveal rearrangements of 22q11.2 region. MLPA confirmed the deletion within the 4q35.2 region. Conclusion: Given the considerable clinical overlaps between the 22q11.2 deletion syndrome and clinical manifestation of the patient described in this study, we propose that region 4q34.1-q35.2 should be considered as another region associated with phenotype resembling 22q11.2 deletion syndrome. We also propose that distal 4q deletions should be considered in the evaluation of patients with phenotypic manifestations resembling 22q11.2 deletion syndrome in whom no 22q11.2 microdeletion was detected, even in the absence of distinctive fifth finger anomalies. Additionally, we underline the importance of applying array CGH that enables simultaneous genome-wide detection and delineation of copy number changes (e.g., deletions and duplications). PMID:21833498

Cuturilo, Goran; Menten, Björn; Krstic, Aleksandar; Drakulic, Danijela; Jovanovic, Ida; Parezanovic, Vojislav; Stevanovic, Milena

2011-11-01

76

Mapping Cortical Morphology in Youth with Velocardiofacial (22q11.2 Deletion) Syndrome  

ERIC Educational Resources Information Center

Objective: Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) represents one of the highest known risk factors for schizophrenia. Insofar as up to 30% of individuals with this genetic disorder develop schizophrenia, VCFS constitutes a unique, etiologically homogeneous model for understanding the pathogenesis of schizophrenia. Method:…

Kates, Wendy R.; Bansal, Ravi; Fremont, Wanda; Antshel, Kevin M.; Hao, Xuejun; Higgins, Anne Marie; Liu, Jun; Shprintzen, Robert J.; Peterson, Bradley S.

2011-01-01

77

Del 1p36 syndrome: a newly emerging clinical entity.  

PubMed

Monosomy 1p36 is a recently delineated contiguous gene syndrome, which is now considered to be the most common subtelomeric microdeletion syndrome. From the recent literature it appears as if 1p36 deletions account for 0.5-1.2% of idiopathic mental retardation. The deletions can be detected by high resolution cytogenetic studies in a minority of patients, and fluorescence in situ hybridisation (FISH) is required in most. The deletions' parent of origin seems still unclear, although in one large series it was shown to be maternal. 1p36 deletion syndrome is characterized by distinct craniofacial features, associated with developmental delay/mental retardation, hypotonia, muscle hypotrophy, seizures, brain abnormalities, and heart defects. To help child neurologists and other professionals in the recognition of this emerging and common chromosomal syndrome, we have reviewed published articles on patients with this deletion. PMID:16023552

Battaglia, Agatino

2005-08-01

78

Effects of Comt Genotype on Behavioral Symptomatology in the 22q11.2 Deletion Syndrome  

Microsoft Academic Search

The 22q11.2 Deletion Syndrome (DiGeorge\\/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in

Carrie E. Bearden; Abbas F. Jawad; David R. Lynch; John R. Monterossso; Set Sokol; Donna M. McDonald-McGinn; Sulagna C. Saitta; Stacy E. Harris; Edward Moss; Paul P. Wang; Elaine Zackai; Beverly S. Emanuel; Tony J. Simon

2005-01-01

79

Neuropsychological Profile and Neuroimaging in Patients with 22Q11.2 Deletion Syndrome: A Review Keywords  

Microsoft Academic Search

22q11.2 Deletion Syndrome is associated with cognitive, behavioural, and psychiatric problems and is known to affect brain structure. Recently, 22q11.2 Deletion Syndrome has been proposed as a disease model for a genetic subtype of schizophrenia. In this paper we discuss the currently available literature on neurocognitive functioning and brain anatomy in patients with 22q11.2 Deletion Syndrome, and how this contributes

Janneke Zinkstok; Thérèse van Amelsvoort

2005-01-01

80

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. © 2014 Wiley Periodicals, Inc. PMID:24668863

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

2014-06-01

81

RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy.  

PubMed

Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be withinRBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case. PMID:23958593

Nakayama, Tojo; Saitsu, Hirotomo; Endo, Wakaba; Kikuchi, Atsuo; Uematsu, Mitsugu; Haginoya, Kazuhiro; Hino-Fukuyo, Naomi; Kobayashi, Tomoko; Iwasaki, Masaki; Tominaga, Teiji; Kure, Shigeo; Matsumoto, Naomichi

2014-06-01

82

Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion.  

PubMed

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki-Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki-Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented. PMID:15702131

Brémond-Gignac, Dominique; Crolla, John A; Copin, Henri; Guichet, Agnès; Bonneau, Dominique; Taine, Laurence; Lacombe, Didier; Baumann, Clarisse; Benzacken, Brigitte; Verloes, Alain

2005-04-01

83

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome  

PubMed Central

Background 22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS. Methods The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43?±?2.23 years after baseline temperament assessment. Results Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS. Conclusions Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.

2014-01-01

84

Chromosome 20 deletions in myelodysplastic syndromes and Philadelphia-chromosome-negative myeloproliferative disorders: characterization by molecular cytogenetics of commonly deleted and retained regions  

Microsoft Academic Search

Deletion of the long arm of chromosome 20 is a recurrent abnormality observed in myelodysplastic syndromes (MDS) and in Philadelphia-chromosome-negative\\u000a myeloproliferative disorders (MPD). Our objective was to characterize the deletion size among 38 MDS and MPD patients using\\u000a fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) probes and to define commonly deleted\\u000a and retained regions on chromosome 20.

Nathalie Douet-Guilbert; Audrey Basinko; Frédéric Morel; Marie-Josée Le Bris; Valérie Ugo; Patrick Morice; Christian Berthou; Marc De Braekeleer

2008-01-01

85

Angelman syndrome: Validation of molecular cytogenetic analysis of chromosome 15q11-q13 for deletion detection  

SciTech Connect

In a series of 18 individuals comprising parents of Angelman syndrome (AS) patients and AS patients with large deletions, microdeletions, and no deletions, we utilized fluorescence in situ hybridization (FISH) with genomic phage clones for loci D15S63 and GABRB3 for deletion detection of chromosome 15q11-q13. Utilization of probes at these loci allows detection of common large deletions and permits discrimination of less common small deletions. In all individuals the molecular cytogenetic data were concordant with the DNA deletion analyses. FISH provides an accurate method of deletion detection for chromosome 15q11-q13. 23 refs., 2 figs., 1 tab.

White, L.; Knoll, J.H.M. [Harvard Medical School, Boston, MA (United States)

1995-03-13

86

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

87

Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients  

Microsoft Academic Search

We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis\\u000a syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified\\u000a in a dual-beam flow cytometer. For each patient, the position of the peak representing the deleted chromosome 17 was compared\\u000a to those of the normal homologs

Barbara J. Trask; Heather Mefford; Ger van den Engh; Hillary F. Massa; Ramesh C. Juyal; Lorraine Potocki; Brenda Finucane; Dianne N. Abuelo; David R. Witt; Ellen Magenis; Antonio Baldini; Frank Greenberg; James R. Lupski; Pragna I. Patel

1996-01-01

88

Multi-exon deletions of the FBN1 gene in Marfan syndrome  

Microsoft Academic Search

BACKGROUND: Mutations in the fibrillin -1 gene (FBN1) cause Marfan syndrome (MFS), an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion. METHODS: We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints,

Wanguo Liu; Iris Schrijver; Thomas Brenn; Heinz Furthmayr; Uta Francke

2001-01-01

89

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

90

A patient with 22q11.2 deletion syndrome: case report.  

PubMed

22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia. PMID:21274400

Ery?lmaz, Sema Kabata?; Ba?, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Rüveyde; Günöz, Hülya; Saka, Nurçin

2009-01-01

91

A Patient with 22q11.2 Deletion Syndrome: Case Report  

PubMed Central

22q11 deletion is one of the most frequently encountered genetic syndromes. The phenotypic spectrum shows a wide variability. We report a boy who presented at age 11.9 years with seizures due to hypocalcemia as a result of hypoparathyroidism. FISH analysis revealed a heterozygote deletion at 22q11.2. Positive findings for the syndrome were delayed speech development due to velofacial dysfunction, recurrent croup attacks in early childhood due to latent hypocalcemia and mild dysmorphic features. The findings of this patient indicate that 22q11 deletion syndrome may present with a wide spectrum of clinical findings and that this diagnosis needs to be considered even in patients of older ages presenting with hypocalcemia. Conflict of interest:None declared.

Bas, Firdevs; Satan, Ali; Darendeliler, Feyza; Bundak, Ruveyde; Gunoz, Hulya; Saka, Nurcin

2009-01-01

92

Unbalanced 3;22 translocation with 22q11 and 3p deletion syndrome.  

PubMed

This report describes a 25-day-old Turkish boy with unbalanced 3;22 translocation that includes the 22q11.2 deletion and 3p25 deletion syndrome. The karyotype was 45, XY,der(3)t(3;22)(p25;q11),-22. Although no immunological dysfunction could be demonstrated, the boy presented some manifestations of DiGeorge anomaly (DGA), which has been associated with monosomy for the same region of chromosome 22, velocardiofacial syndrome (VCFS), and the 3p deletion syndrome. Clinical features include short stature, hypertelorism, low set ears, cleft lip with cleft palate, short neck, truncus arteriosus, micropenis, clubfoot, over riding toes on right foot, four digits on left foot and growth delay. In addition he had feeding difficulties, respiratory infections, and developmental delay. Fluorescence in situ hybridization (FISH) studies confirmed loss of the proximal DiGeorge chromosomal region (DGCR). Array CGH analysis showed the deletion sites on chromosomes 3 and 22. This report documents a rare chromosomal aberration that causes the 22q11 and 3p deletion syndrome simultaneously. PMID:20949503

Dundar, Munis; Kiraz, Aslihan; Tasdemir, Sener; Akalin, Hilal; Kurtoglu, Selim; Hafo, Filiz; Cine, Naci; Savli, Hakan

2010-11-01

93

Primary Amenorrhea and Absent Uterus in the 22q11.2 Deletion Syndrome  

PubMed Central

The classic clinical features in the 22q11.2 deletion syndrome are congenital heart defects, hypocalcemia, immunodeficiency, learning, speech, and behavioral difficulties. The phenotype is highly variable and continues to expand. We present two cases of absent uterus and unilateral renal agenesis in females with the 22q11.2 deletion. Clinicians caring for these adolescents should be aware of the possibility of renal anomalies and Mullerian agenesis. The diagnosis of 22q11.2 deletion may be considered in a female with Mullerian agenesis, particularly, in association with a history of learning difficulties and speech delay.

Sundaram, Usha T.; McDonald-McGinn, Donna M.; Huff, Dale; Emanuel, Beverly S.; Zackai, Elaine H.; Driscoll, Deborah A.; Bodurtha, Joann

2010-01-01

94

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes  

SciTech Connect

We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered. 41 refs., 4 figs., 2 tabs.

Teshima, I.; Chadwick, D.; Chitayat, D. [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)] [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)

1996-03-29

95

Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes  

PubMed Central

Prader–Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1–BP3 and BP2–BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n=5) or larger (n=2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in ?8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

Kim, Soo-Jeong; Miller, Jennifer L; Kuipers, Paul J; German, Jennifer Ruth; Beaudet, Arthur L; Sahoo, Trilochan; Driscoll, Daniel J

2012-01-01

96

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.  

PubMed

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia. PMID:16234808

Gothelf, Doron; Eliez, Stephan; Thompson, Tracy; Hinard, Christine; Penniman, Lauren; Feinstein, Carl; Kwon, Hower; Jin, Shuting; Jo, Booil; Antonarakis, Stylianos E; Morris, Michael A; Reiss, Allan L

2005-11-01

97

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

98

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

99

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

PubMed Central

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 (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) 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. Images Figure 2

Juyal, R. C.; Figuera, L. E.; Hauge, X.; Elsea, S. H.; Lupski, J. R.; Greenberg, F.; Baldini, A.; Patel, P. I.

1996-01-01

100

22q11 Deletion Syndrome: A Role for TBX1 in Pharyngeal and Cardiovascular Development  

Microsoft Academic Search

Tbx1 is a member of the Tbox family of binding domain transcription factors. TBX1 maps within the region of 22q11 deleted in humans with DiGeorge or velocardiofacial syndrome. Mice haploinsufficient for\\u000a Tbx1 have phenotypes that recapitulate major features of the syndrome, notably abnormal growth and remodelling of the pharyngeal\\u000a arch arteries. The Tbx1 haploinsufficiency phenotype is modified by genetic background

Peter J. Scambler

2010-01-01

101

Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome  

Microsoft Academic Search

AimsAlthough poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome.MethodsClinical and laboratory parameters from 64 patients with 22q11.2

A. Herwadkar; A. R. Gennery; A. S. Moran; M. R. Haeney; P. D. Arkwright

2010-01-01

102

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.

2012-01-01

103

Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: Evaluation of 235 patients  

SciTech Connect

Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as {open_quotes}classic{open_quotes} (n = 114) or{open_quotes}uncertain{close_quotes} (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS. 14 refs., 2 figs., 4 tabs.

Lowery, M.C.; Brothman, L.J.; Leonard, C.O. [Univ. of Utah Health Sciences Center, Salt Lake City, UT (United States)] [and others

1995-07-01

104

Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients.  

PubMed Central

Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as "classic" (n = 114) or "uncertain" (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS. Images Figure 1 Figure 2

Lowery, M C; Morris, C A; Ewart, A; Brothman, L J; Zhu, X L; Leonard, C O; Carey, J C; Keating, M; Brothman, A R

1995-01-01

105

Human Subtelomeric WASH Genes Encode a New Subclass of the WASP Family  

PubMed Central

Subtelomeres are duplication-rich, structurally variable regions of the human genome situated just proximal of telomeres. We report here that the most terminally located human subtelomeric genes encode a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome Protein family, whose known members reorganize the actin cytoskeleton in response to extracellular stimuli. This new subclass, which we call WASH, is evolutionarily conserved in species as diverged as Entamoeba. We demonstrate that WASH is essential in Drosophila. WASH is widely expressed in human tissues, and human WASH protein colocalizes with actin in filopodia and lamellipodia. The VCA domain of human WASH promotes actin polymerization by the Arp2/3 complex in vitro. WASH duplicated to multiple chromosomal ends during primate evolution, with highest copy number reached in humans, whose WASH repertoires vary. Thus, human subtelomeres are not genetic junkyards, and WASH's location in these dynamic regions could have advantageous as well as pathologic consequences.

Linardopoulou, Elena V; Parghi, Sean S; Friedman, Cynthia; Osborn, Gregory E; Parkhurst, Susan M; Trask, Barbara J

2007-01-01

106

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.

2014-01-01

107

Deletion of short arm of chromosome 18, Del(18p) syndrome.  

PubMed

Deletion of the short arm of chromosome 18 is a rare syndrome clinically presenting with variable mental retardation, growth retardation, low height, pectus excavatum, craniofacial malformations including long ear, ptosis, microcephaly and short neck. This case report presents with characteristic features along with rare feature of single nostril. PMID:24531606

Babaji, Prashant; Singh, Anurag; Lau, Himani; Lamba, G; Somasundaram, P

2014-01-01

108

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

109

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

110

22q11.2 deletion syndrome with life-threatening adenovirus infection.  

PubMed

Adenovirus causes significant morbidity and mortality in immunocompromised children. We report how an infusion of HLA-matched sibling donor T lymphocytes rapidly eradicated life-threatening, high-level adenoviremia in a child with complete DiGeorge syndrome (22q11.2 deletion) who went on to reconstitute a diverse, donor-derived, postthymic T-cell repertoire. PMID:23660376

Ip, Winnie; Zhan, Hong; Gilmour, Kimberly C; Davies, E Graham; Qasim, Waseem

2013-09-01

111

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

112

The Diverse Clinical Features of Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome).  

PubMed

A 2-year-old boy with chromosome 22q11.2 deletion syndrome was referred for recurrent sinopulmonary infections. He was diagnosed shortly after birth by a fluorescence in situ hybridization test that was performed due to interrupted aortic arch type B. He had no hypocalcemia, and his recovery from cardiac repair was uneventful. He had difficulty feeding and gained weight slowly, but, otherwise, there were no concerns during his first year of life. At 15 months of age, he began to develop significant otitis media and bronchitis. He was hospitalized once for pneumonia at 18 months of age and has never been off antibiotics for more than 1 week since then. He has not had any previous immunologic evaluation. Recurrent sinopulmonary infections in a child with chromosome 22q11.2 deletion syndrome can have the same etiologies as in any other child. Atopy, anatomic issues, cystic fibrosis, and new environmental exposures could be considered in this setting. Early childhood can be problematic for patients with chromosome 22q11.2 deletion syndrome due to unfavorable drainage of the middle ear and sinuses. Atopy occurs at a higher frequency in 22q11.2 deletion syndrome, and these children also have a higher rate of gastroesophageal reflux and aspiration than the general population. As would be appropriate for any child who presents with recurrent infections at 2 years of age, an immunologic evaluation should be performed. In this review, we will highlight recent findings and new data on the management of children and adults with chromosome 22q11.2 deletion syndrome. PMID:24565705

Maggadottir, Solrun Melkorka; Sullivan, Kathleen E

2013-01-01

113

EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients.  

PubMed

Lynch syndrome, one of the most common cancer susceptibility syndromes, is caused by germline mutations of genes affecting the mismatch repair proteins MLH1, MSH2, MSH6 or PMS2. Most of these mutations disrupt the open reading frame of the genes involved and, as such, lead to constitutive inactivation of the mutated allele. In a subset of Lynch syndrome patients MSH2 was found to be specifically inactivated in cell lineages exhibiting EPCAM expression. These patients carry deletions of the 3' end of the EPCAM gene, including its polyadenylation signal. Due to concomitant transcriptional read-through of EPCAM, the promoter of MSH2 15 kb further downstream becomes inactivated through hypermethylation. As these 3' EPCAM deletions occur in the germline, this MSH2 promoter methylation ('epimutation') is heritable. Worldwide, numerous EPCAM 3' end deletions that differ in size and location have been detected. The risk of colorectal cancer in carriers of such EPCAM deletions is comparable to that of MSH2 mutation carriers, and is in accordance with a high expression of EPCAM in colorectal cancer stem cells. The risk of endometrial cancer in the entire group of EPCAM deletion carriers is significantly lower than that in MSH2 mutation carriers, but the actual risk appears to be dependent on the size and location of the EPCAM deletion. These observations may have important implications for the surveillance of EPCAM deletion carriers and, thus, calls for an in-depth assessment of clinically relevant genotype-phenotype correlations and its underlying molecular mechanism(s). PMID:23264089

Ligtenberg, Marjolijn J L; Kuiper, Roland P; Geurts van Kessel, Ad; Hoogerbrugge, Nicoline

2013-06-01

114

Attenuated Positive Symptoms of Psychosis in Adolescents with Chromosome 22q11.2 Deletion Syndrome  

PubMed Central

Thirty percent of individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder, particularly schizophrenia. We assessed attenuated positive, negative and disorganized symptoms of psychosis and clinical-high-risk syndromes in 20 adolescents with 22q11.2DS (median age 15.1 years) using the Structured Interview for Prodromal Symptoms (SIPS). Two participants met criteria for the Attenuated Positive Symptom Syndrome, while nine participants (45%) experienced positive symptoms rated in the “moderate” to “severe and psychotic” range on the SIPS. Almost all presented with moderate to severe symptoms in the negative, disorganized, and general symptom domains.

Stoddard, Joel; Niendam, Tara; Hendren, Robert; Carter, Cameron; Simon, Tony J.

2010-01-01

115

EPCAM Germ Line Deletions as Causes of Lynch Syndrome in Spanish Patients  

PubMed Central

The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-five cases with MSH2 loss were identified: 10 had mutations of MSH2, five had mutations of MSH6, and 10 did not show MSH2/MSH6 mutations. These 25 cases were analyzed for EPCAM deletions using multiplex ligation-dependent probe amplification, and deletions were mapped using long-range PCR analysis. One subject with no MSH2/MSH6 mutations had a large deletion in the EPCAM locus that extended for 8.7 kb and included exons 8 and 9. The tumor exhibited MSH2 promoter hypermethylation. EPCAM deletion analysis followed by MSH2 methylation testing of the tumor is a fast low-cost procedure that can be used to identify mutations that cause LS. We propose that this procedure be incorporated into clinical genetic analysis strategies and present a decision-support flow diagram for the diagnosis of LS.

Guarinos, Carla; Castillejo, Adela; Barbera, Victor-Manuel; Perez-Carbonell, Lucia; Sanchez-Heras, Ana-Beatriz; Segura, Angel; Guillen-Ponce, Carmen; Martinez-Canto, Ana; Castillejo, Maria-Isabel; Egoavil, Cecilia-Magdalena; Jover, Rodrigo; Paya, Artemio; Alenda, Cristina; Soto, Jose-Luis

2010-01-01

116

Screening for subtelomeric rearrangements using genetic markers in 70 patients with unexplained mental retardation.  

PubMed

Cryptic unbalanced rearrangements involving chromosome ends are a significant cause of idiopathic mental retardation. The most frequently used technique to screen for these subtle rearrangements is Multiprobe fluorescence in situ hybridization (FISH). As this is a labor-intensive technique, we used microsatellite genotyping to detect possible subtelomeric rearrangements in a study population. Out of the 70 patients we screened, three chromosomal rearrangements were detected: a deletion of marker D2S2986, a deletion of marker D7S594 and a deletion of marker D19S424. However, none of these aberrations appeared to be disease causing. PMID:15050874

Rooms, Liesbeth; Reyniers, Edwin; van Luijk, Rob; Scheers, Stefan; Wauters, Jan; Kooy, R Frank

2004-01-01

117

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.

2014-01-01

118

Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review  

PubMed Central

Chronic Granulomatous Disease (CGD), a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans). Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB), located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.

2011-01-01

119

Aortic Root Dilation in Patients With 22q11.2 Deletion Syndrome  

PubMed Central

The 22q11.2 deletion syndrome is characterized by a highly variable phenotype including a range of cardiac malformations. The most common cardiovascular features include a subset of conotruncal defects, perimembranous ventricular septal defects and aortic arch anomalies. This report describes a series of patients with 22q11.2 deletion syndrome with the novel cardiac finding of mild aortic root dilation. A chart review was performed on 93 patients with documented 22q11.2 deletion without significant congenital heart disease to determine the number of patients with aortic root dilation. Patients ranged in age from 1 to 13 years of age. Of these 93 patients, 10 patients were found to have aortic root dilation on a screening echocardiogram. Seven of these patients did not have any additional risk factors while three patients had a bicuspid aortic valve (BAV). Four of 10 patients had additional minor cardiac anomalies including repaired ventricular septal defect (1), patent ductus arteriosus(1), arch anomalies (1), and left pulmonary artery stenosis (1). Three patients had isolated cases of aortic root dilation. Interestingly, several of these patients did not have aortic root dilation on their initial echocardiograms. The purpose of this study is to draw attention to a novel cardiac finding in patients with 22q11.2 deletion that may be of clinical importance. Further long-term study is warranted to assess the need for echocardiographic screening in the 22q11.2 deleted population for aortic root dilation into adolescence and adulthood.

John, Anitha S.; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Goldmuntz, Elizabeth

2014-01-01

120

LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome  

PubMed Central

Background LKB1/STK11 germline mutations cause Peutz?Jeghers syndrome (PJS). The existence of a second PJS locus is controversial, the evidence in its favour being families unlinked to LKB1 and the low frequency of LKB1 mutations found using conventional methods in several studies. Exonic and whole gene deletion or duplication events cannot be detected by routine mutation screening methods. Objective To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening. Methods From an original cohort of 76 patients, 48 were found to have a germline mutation by direct sequencing; the remaining 28 were examined using multiplex ligation dependent probe amplification (MLPA) analysis to detect LKB1 copy number changes. Results Deletions were found in 11 of the 28 patients (39%)—that is, 14% of all PJS patients (11/76). Five patients had whole gene deletions, two had the promoter and exon 1 deleted, and in one patient exon 8 was deleted. Other deletions events involved: loss of exons 2–10; deletion of the promoter and exons 1–3; and loss of part of the promoter. No duplications were detected. Nine samples with deletions were sequenced at reported single nucleotide polymorphisms to exclude heterozygosity; homozygosity was found in all cases. No MLPA copy number changes were detected in 22 healthy individuals. Conclusions These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76). It is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of PJS patients in clinical practice.

Volikos, E; Robinson, J; Aittomaki, K; Mecklin, J-P; Jarvinen, H; Westerman, A M; de Rooij, F W M; Vogel, T; Moeslein, G; Launonen, V; Tomlinson, I P M; Silver, A R J

2006-01-01

121

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

122

Novel deletion mutation of TRPS1 gene in a Chinese patient of trichorhinophalangeal syndrome type I.  

PubMed

Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant disorder. Deletion or mutation of the TRPS1 gene leads to the tricho-rhino-phalangeal syndromes type I or type III. In this article, we describe a Chinese patient affected with type I TRPS and showing prominent pilar, rhinal and phalangeal abnormalities. Mutational screening and sequence analysis of TRPS1 gene revealed a previously unidentified four-base-pair deletion of nucleotides 1783-1786 (c.1783_1786delACTT). The mutation causes a frame shift after codon 593, introducing a premature stop codon after 637 residues in the gene sequence. This deletion is an unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that sparse hair and metacarpal defects of tricho-rhino-phalangeal syndromes in this patient are due to this TRPS1 mutation. And this data further supports the critical role of TRPS1 gene in hair and partial skeleton morphogenesis. PMID:23510776

Nan, Xu; Dai, Shan; Li, Chun-ting; Chen, Xue-rong; Zhao, Hong-shan; Zhang, Feng-shan; Song, Qing-hua

2013-07-01

123

Two novel gross deletions of TSC2 in Malaysian patients with tuberous sclerosis complex and TSC2/PKD1 contiguous deletion syndrome.  

PubMed

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder affecting multiple organs. Tuberous sclerosis complex is caused by mutation in either one of the two disease-causing genes, TSC1 or TSC2, encoding for hamartin and tuberin, respectively. TSC2/PKD1 contiguous gene deletion syndrome is a very rare condition due to deletion involving both TSC2 and PKD1 genes. Tuberous sclerosis complex cannot be easily diagnosed since there is no pathognomonic feature, although there are consensus diagnostic criteria for that. Mutation analysis is useful and plays important roles. We report here two novel gross deletions of TSC2 gene in Malay patients with tuberous sclerosis complex and TSC2/PKD1 contiguous gene deletion syndrome, respectively. PMID:24683199

Ismail, Nur Farrah Dila; Nik Abdul Malik, Nik Mohd Ariff; Mohseni, Jafar; Rani, Abdulqawee Mahyoob; Hayati, Fatemeh; Salmi, Abdul Razak; Narazah, Mohd Yusof; Zabidi-Hussin, Z A M H; Silawati, Abdul Rashid; Keng, Wee Teik; Ngu, Lock Hock; Sasongko, Teguh Haryo

2014-05-01

124

Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms  

Microsoft Academic Search

Interstitial deletion of 7q11.23–q21.11 was identified by cytogenetic methods in a 4-year-old boy with Williams syndrome\\u000a (WS) and infantile spasms. Deletion of the elastin (ELN) gene and the DNA polymorphic markers, D7S1870, D7S2490, D7S2518, and D7S2421, were identified in the patient, but the loci\\u000a for D7S653 and D7S675 were not involved. Zackowski et al. (1990) reported that 6 of 16

Kiyomi Mizugishi; Keiko Yamanaka; Katsuko Kuwajima; Ikuko Kondo

1998-01-01

125

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.

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

2013-01-01

126

An Fgf8 Mouse Mutant Phenocopies Human 22q11 Deletion Syndrome  

PubMed Central

SUMMARY Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.

Frank, Deborah U.; Fotheringham, Lori K.; Brewer, Judson A.; Muglia, Louis J.; Tristani-Firouzi, Martin; Capecchi, Mario R.; Moon, Anne M.

2006-01-01

127

Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome  

Microsoft Academic Search

Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the development of schizophrenia are unclear. We sought to delineate midline neuroanatomical abnormalities in nonpsychotic children with 22q11DS and their age- and sex-matched controls and compare these

Vandana Shashi; Srirangam Muddasani; Cesar C. Santos; Margaret N. Berry; Thomas R. Kwapil; Eve Lewandowski; Matcheri S Keshavan

2004-01-01

128

Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease  

Microsoft Academic Search

Kearns Sayre syndrome (KSS) is a multisystem disorder with a confounding variety of clinical manifestations, including ocular\\u000a myopathy, pigmentary retinopathy, heart block and ataxia. Endocrinopathies are common in KSS, including growth hormone deficiency,\\u000a hypogonadism, diabetes mellitus and hypoparathyroidism. ?A variety of deletions of mitochondrial DNA (mtDNA) are found in\\u000a most cases. We report on a 5-year-old boy with Addison disease

R. G. Boles; T. Roe; D. Senadheera; V. Mahnovski; L. J. C. Wong

1998-01-01

129

Large genomic fibrillin-1 ( FBN1 ) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome  

Microsoft Academic Search

Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable\\u000a manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and\\u000a duplications. In this

Gábor Mátyás; Sira Alonso; Andrea Patrignani; Myriam Marti; Eliane Arnold; István Magyar; Caroline Henggeler; Thierry Carrel; Beat Steinmann; Wolfgang Berger

2007-01-01

130

Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion  

Microsoft Academic Search

We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(q11-13), spanning markers from D15S9 to D15S12, about 3 center dot 5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11 center dot 2

A Smith; C Wiles; E Haan; J McGill; G Wallace; J Dixon; R Selby; A Colley; R Marks; R J Trent

1996-01-01

131

Recurrence of DiGeorge syndrome: prenatal detection by FISH of a molecular 22q11 deletion.  

PubMed Central

We report on a prenatal diagnosis by FISH of a familial 22q11 deletion associated with DiGeorge syndrome (DGS). The deletion was seen in the proband with symptoms of full DGS, in the physically normal father, and in a subsequent pregnancy. After birth this child showed hypocalcaemia, a T cell deficit, and a right sided aortic arch. Images

Van Hemel, J O; Schaap, C; Van Opstal, D; Mulder, M P; Niermeijer, M F; Meijers, J H

1995-01-01

132

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

133

First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome.  

PubMed

Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1. PMID:22712005

Beygo, J; Buiting, K; Seland, S; Lüdecke, H-J; Hehr, U; Lich, C; Prager, B; Lohmann, D R; Wieczorek, D

2012-01-01

134

Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.  

PubMed Central

Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.

Carlson, C; Sirotkin, H; Pandita, R; Goldberg, R; McKie, J; Wadey, R; Patanjali, S R; Weissman, S M; Anyane-Yeboa, K; Warburton, D; Scambler, P; Shprintzen, R; Kucherlapati, R; Morrow, B E

1997-01-01

135

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.

2014-01-01

136

RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions  

PubMed Central

Background: Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviours, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births. Heterozygous frameshift mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions. Objective: Analysis of four individuals with features consistent with SMS for variations in RAI1, using a polymerase chain reaction and sequencing strategy. None of these patients carry 17p11.2 deletions. Results: Two patients had small deletions in RAI1 resulting in frameshift and premature truncation of the protein. Missense mutations were identified in the other two. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo, as all parental samples were normal. Several polymorphisms were also observed, including new and reported SNPs. The patients' clinical features differed from those found in 17p11.2 deletion by general absence of short stature and lack of visceral anomalies. All four patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioural anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in one patient of the cohort. Conclusions: Haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms.

Girirajan, S; Elsas, L; Devriendt, K; Elsea, S

2005-01-01

137

22q11 deletion syndrome: a review of the neuropsychiatric features and their neurobiological basis  

PubMed Central

The 22q11.2 deletion syndrome (22q11DS) is caused by an autosomal dominant microdeletion of chromosome 22 at the long arm (q) 11.2 band. The 22q11DS is among the most clinically variable syndromes, with more than 180 features related with the deletion, and is associated with an increased risk of psychiatric disorders, accounting for up to 1%–2% of schizophrenia cases. In recent years, several genes located on chromosome 22q11 have been linked to schizophrenia, including those encoding catechol-O-methyltransferase and proline dehydrogenase, and the interaction between these and other candidate genes in the deleted region is an important area of research. It has been suggested that haploinsufficiency of some genes within the 22q11.2 region may contribute to the characteristic psychiatric phenotype and cognitive functioning of schizophrenia. Moreover, an extensive literature on neuroimaging shows reductions of the volumes of both gray and white matter, and these findings suggest that this reduction may be predictive of increased risk of prodromal psychotic symptoms in 22q11DS patients. Experimental and standardized cognitive assessments alongside neuroimaging may be important to identify one or more endophenotypes of schizophrenia, as well as a predictive prodrome that can be preventively treated during childhood and adolescence. In this review, we summarize recent data about the 22q11DS, in particular those addressing the neuropsychiatric and cognitive phenotypes associated with the deletion, underlining the recent advances in the studies about the genetic architecture of the syndrome.

Squarcione, Chiara; Torti, Maria Chiara; Di Fabio, Fabio; Biondi, Massimo

2013-01-01

138

Molecular Definition of the 22q11 Deletions in Velo-Cardio-Facial Syndrome  

PubMed Central

Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers >9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation ImagesFigure 2Figure 3

Morrow, Bernice; Goldberg, Rosalie; Carlson, Christine; Gupta, Ruchira Das; Sirotkin, Howard; Collins, John; Dunham, Ian; O'Donnell, Hilary; Scambler, Peter; Shprintzen, Robert; Kucherlapati, Raju

1995-01-01

139

Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome  

SciTech Connect

Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft plate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers >9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation. 58 refs., 6 figs., 2 tabs.

Morrow, B.; Carlson, C.; Gupta, R.D. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others

1995-06-01

140

Prenatal and postnatal diagnosis of 22q11.2 deletion syndrome.  

PubMed

Microdeletion of chromosome 22q11.2, the most common human deletion syndrome encompasses a wide spectrum of abnormalities. Many clinical or ultrasonographic findings may support deletion studies, either in utero or in the post-natal period. The objective of our study was to evaluate the circumstances of 22q11.2 deletion diagnosis in a single centre of genetics during a 12 years period. Testing for 22q11.2 deletion was performed in 883 cases. Congenital heart defect was the most common reason for referral. An antenatal 22q11.2 microdeletion was detected in 8 fetuses (4.7%) among 169 pregnancies, all presenting conotruncal anomalies. In one case prenatal diagnosis led to the identification of the deletion in the mildly affected father and had negative impact on the family. During the same period, postnatal 22q11.2 DS was diagnosed in 81 out of 714 patients aged from birth to 42 years (11.3%) (p = 0.02). A CHD was present in 37 (45.7%). This figure is significantly lower than the 75% commonly reported. These results suggest that deletion studies could be justifiable in fetuses with non-cardiac prenatal sonographic findings that have been reported in association with 22q11.2 DS. However, as most of these malformations are rather common and non specific, systematic 22q11.2 testing is not justifiable. In such cases, careful cardiac and thymus examination could provide additional clues for 22q11.2 testing. In addition parents should be given accurate information before antenatal or postnatal testing, including the wide variability of the clinical phenotype, the impossibility to establish a precise prognosis concerning psychomotor development and psychiatric risks. PMID:20659598

Bretelle, Florence; Beyer, Laura; Pellissier, Marie Christine; Missirian, Chantal; Sigaudy, Sabine; Gamerre, Marc; D'Ercole, Claude; Philip, Nicole

2010-01-01

141

Deletion at chromosome 16p13. 3 as a cause of Rubinstein-Taybi syndrome: Clinical aspects  

SciTech Connect

In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16p13.3 is described. The authors investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental disomy plays a role in etiology, and (c) to compare clinical features in patients with a deletion to those in individuals in whom deletions were not detectable. Molecular studies showed a copy of chromosome 16 from each parent in all 19 patients. Uniparental disomy was also excluded for five other chromosome arms known to be imprinted in mice. None of the probes used for determining the origin of the deleted chromosome proved to be informative. The clinical features were essentially the same in patients with and without visible deletion, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces. A small deletion at 16p13.3 may be found in some patients with Rubinstein-Taybi syndrome. Cytogenetically undetectable deletions, point mutations, mosaicism, heterogeneity, or phenocopy by a nongenetic cause are the most probable explanations for the absence of cytogenetic or molecular abnormalities in other patients with Rubinstein-Taybi syndrome. 26 refs., 3 tabs., 2 figs.

Hennekam, R.C.M.; Tilanus, M.; Boogaard, M.J.H. van den (State Univ., Utrecht (Netherlands)); Hamel, B.C.J.; Voshart-van Heeren, H.; Mariman, E.C.M.; Beersum, S.E.C. van (University Hospital, Nijmegen (Netherlands)); Breuning, M.H. (Clinical Genetics Center, Rotterdam (Netherlands))

1993-02-01

142

A de novo deletion in X 27-28 spans at least 3 megabases and results in fragile X syndrome  

SciTech Connect

A 2-year-old boy with Martin-Bell syndrome was referred for molecular testing and found to have a large deletion of FMRI. His mother was found to have two FMR-1 alleles in the normal range for CGG repeats. DNA probes located both proximal and distal to FRAXA were used to delineate the approximation location of the deletion endpoints. Proximal to the fragile site, DXS312 (pX135) was absent but DXS98 (4D8) was present. Distal to the fragile site, DXS296 (VK21) was absent but DXS304 (U6.2) was present. Our patient does not appear to have clinical findings other than those typically associated with fragile X syndrome suggesting that the deletion does not remove other contiguous genes, e.g., IDS. The deletion in this patient is larger than the patient reported by Gedeon et al., in whom approximately 2.5 megabases were estimated to be deleted. Using the physical map of Schlessinger et al., the physical extent of the deletion can be estimated to be at least 3 megabases. This patient may be useful in physical mapping of the chromosomal region near FMR-1. Continued long-term evaluation of this patient may uncover clinical findings suggestive that the deletion removes other genes near to FMR-1 or, alternatively, no findings atypical of the fragile X syndrome suggesting that no other genes lie in the deletion interval.

Lachiewicz, A.; Rao, K.; Aylsworth, A.; Richie, R.; Schwartz, C.; Tarleton, J. [Duke Univ. Medical Center, Durham, NC (United States)]|[Univ. of North Carolina, Chapel Hill, NC (United States)]|[Greenwood Genetic Center, NC (United States)

1994-07-15

143

Subtelomeric rearrangements in the mentally retarded: a comparison of detection methods.  

PubMed

In recent years, subtelomeric rearrangements, e.g., chromosome deletions or duplications too small to be detected by conventional cytogenetic analysis, have emerged as a significant cause of both idiopathic and familial mental retardation. As mental retardation is a common disorder, many patients need to be tested on a routine basis. In this review, we will discuss the different methods that have been applied in laboratories worldwide, including multiprobe fluorescence in situ hybridization (FISH), multiallelic marker analysis, multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), quantitative real-time PCR, comparative genomic hybridization (CGH), and multicolor FISH, including spectral karyotyping (SKY), subtelomeric combined binary ratio labeling FISH (S-COBRA FISH), multiplex FISH telomere integrity assay (M-TEL), telomeric multiplex FISH (TM-FISH), and primed in situ labeling (PRINS). PMID:15880643

Rooms, Liesbeth; Reyniers, Edwin; Kooy, R Frank

2005-06-01

144

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

145

PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females  

PubMed Central

In a 16-year-old girl with intellectual disability, irregular teeth, slight body asymmetry, and striated skin pigmentation, highly skewed X-inactivation increased the likelihood of an X-linked cause of her condition. Among these, prominent supraorbital ridges and hearing loss suggested a filaminopathy, but no filamin A mutation was found. The correct diagnosis, Borjeson-Forssman-Lehmann syndrome (BFLS, MIM#301900), was first made when a copy number array identified a de novo 15-kb deletion of the terminal 3 exons of the PHF6 gene. In retrospect, her phenotype resembled that of males with BFLS. Such deletions of PHF6 have not been reported previously. This might be because PHF6 mutations are rarely looked for in females since classical BFLS so far has been thought to be a male-specific syndrome, and large PHF6 deletions might be incompatible with male fetal survival. If this is the case, sporadic BFLS could be more frequent in females than in males.

Berland, S.; Alme, K.; Brendehaug, A.; Houge, G.; Hovland, R.

2011-01-01

146

Overlapping Numerical Cognition Impairments in Children with Chromosome 22q11.2 Deletion or Turner Syndromes  

ERIC Educational Resources Information Center

Children with one of two genetic disorders (chromosome 22q11.2 deletion syndrome and Turner syndrome) as well typically developing controls, participated in three cognitive processing experiments. Two experiments were designed to test cognitive processes involved in basic aspects numerical cognition. The third was a test of simple manual motor…

Simon, T. J.; Takarae, Y.; DeBoer, T.; McDonald-McGinn, D. M.; Zackai, E. H.; Ross, J. L.

2008-01-01

147

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

148

Rubinstein-Taybi syndrome with deletions of FISH probe RT1 at 16p13.3: two UK patients  

Microsoft Academic Search

We report two patients with Rubinstein-Taybi syndrome out of a total of 16 tested who have a deletion of the region visualised by the cosmid probe RT1. These results further confirm this as a locus for Rubinstein-Taybi syndrome.

J M McGaughran; L Gaunt; J Dore; F Petrij; H G Dauwerse; D Donnai

1996-01-01

149

miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome  

PubMed Central

In humans, the most common genomic disorder is a hemizygous deletion of a 1.5–3 Mb region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20–25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.

Brzustowicz, Linda M.; Bassett, Anne S.

2012-01-01

150

Molecular definition of the shortest region of deletion overlap in the Langer-Giedion syndrome  

PubMed Central

The Langer-Giedion syndrome (LGS), which is characterized by craniofacial dysmorphism and skeletal abnormalities, is caused by a genetic defect in 8q24.1. We have used 13 anonymous DNA markers from an 8q24.1-specific microdissection library, as well as c-myc and thyroglobulin gene probes, to map the deletion breakpoints in 16 patients with LGS. Twelve patients had a cytogenetically visible deletion, two patients had an apparently balanced translocation, and two patients had an apparently normal karyotype. In all cases except one translocation patient, loss of genetic material was detected. The DNA markers fall into 10 deletion intervals. Clone L48 (D8S51) defines the shortest region of deletion overlap (SRO), which is estimated to be less than 2 Mbp. Three clones–pl7-2.3EE (D8S43), L24 (D8S45), and L40 (D8S49)–which flank the SRO recognize evolutionarily conserved sequences. ImagesFigure 1Figure 3Figure 4

Ludecke, Hermann-Josef; Johnson, Carey; Wagner, Michael J.; Wells, Dan E.; Turleau, Catherine; Tommerup, Niels; Latos-Bielenska, Anna; Sandig, Klaus-Rainer; Meinecke, Peter; Zabel, Bernhard; Horsthemke, Bernhard

1991-01-01

151

Critical region in 2q31.2q32.3 deletion syndrome: Report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region  

PubMed Central

Background Standard cytogenetic analysis has revealed to date more than 30 reported cases presenting interstitial deletions involving region 2q31-q32, but with poorly defined breakpoints. After the postulation of 2q31.2q32.3 deletion as a clinically recognizable disorder, more patients were reported with a critical region proposed and candidate genes pointed out. Results We report two female patients with de novo chromosome 2 cytogenetically visible deletions, one of them with an additional de novo deletion in chromosome 20p12.2p12.3. Patient I presents a 16.8?Mb deletion in 2q31.2q32.3 while patient II presents a smaller deletion of 7?Mb in 2q32.1q32.3, entirely contained within patient I deleted region, and a second 4?Mb deletion in Alagille syndrome region. Patient I clearly manifests symptoms associated with the 2q31.2q32.3 deletion syndrome, like the muscular phenotype and behavioral problems, while patient II phenotype is compatible with the 20p12 deletion since she manifests problems at the cardiac level, without significant dysmorphisms and an apparently normal psychomotor development. Conclusions Whereas Alagille syndrome is a well characterized condition mainly caused by haploinsufficiency of JAG1 gene, with manifestations that can range from slight clinical findings to major symptoms in different domains, the 2q31.2q32.3 deletion syndrome is still being delineated. The occurrence of both imbalances in reported patient II would be expected to cause a more severe phenotype compared to the individual phenotype associated with each imbalance, which is not the case, since there are no manifestations due to the 2q32 deletion. This, together with the fact that patient I deleted region overlaps previously reported cases and patient II deletion is outside this common region, reinforces the existence of a critical region in 2q31.3q32.1, between 181 to 185?Mb, responsible for the clinical phenotype.

2012-01-01

152

Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4  

PubMed Central

Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15–35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.

Bondurand, Nadege; Fouquet, Virginie; Baral, Viviane; Lecerf, Laure; Loundon, Natalie; Goossens, Michel; Duriez, Benedicte; Labrune, Philippe; Pingault, Veronique

2012-01-01

153

Longitudinal Analysis of Lymphocyte Function and Numbers in the First Year of Life in Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome\\/Velocardiofacial Syndrome)  

Microsoft Academic Search

Chromosome 22q11.2 deletion syndrome is a common syndrome typically consisting of variable cardiac defects, hypoparathyroidism, developmental delay, and immunodeficiency. The hemizygous deletion has vari- able effects on the immune system even within the same kindred, and the extent of the immunodeficiency is difficult to predict. Some patients have shown improvement over time; however, this is the first prospective longitudinal study

KATHLEEN E. SULLIVAN; DONNA MCDONALD-MCGINN; DEBORAH A. DRISCOLL; BEVERLY S. EMANUEL; ELAINE H. ZACKAI; ABBAS F. JAWAD

1999-01-01

154

Interstitial deletion of 11q-implicating the KIRREL3 gene in the neurocognitive delay associated with Jacobsen syndrome.  

PubMed

Jacobsen syndrome (JS) is a rare contiguous gene disorder characterized by a deletion within the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. The clinical findings include characteristic dysmorphic features, growth and psychomotor delays and developmental anomalies involving the brain, eyes, heart, kidneys, immune, hematologic, endocrine, and gastrointestinal systems. The majority of cases are due to a terminal deletion of 11q; however interstitial deletions have also been reported. We report on a child with clinical manifestations consistent with JS who had a 2.899 Mb interstitial deletion at 11q24.2-q24.3 which is the smallest interstitial deletion reported so far to our knowledge. This deletion includes the KIRREL3 gene, and given our patient's history of neurocognitive delay and autism spectrum disorder, it raises the possibility that this gene is a candidate for the social and expressive language delay observed in our patient. PMID:22965935

Guerin, Andrea; Stavropoulos, Dimitri J; Diab, Yaser; Chénier, Sébastien; Christensen, Hilary; Kahr, Walter H A; Babul-Hirji, Riyana; Chitayat, David

2012-10-01

155

A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Gouti?res syndrome associated with mtDNA deletions  

PubMed Central

Aicardi–Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLG?, POLG?, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9?kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components.

Leshinsky-Silver, Esther; Malinger, Gustavo; Ben-Sira, Liat; Kidron, Dvora; Cohen, Sarit; Inbar, Shani; Bezaleli, Tali; Levine, Arie; Vinkler, Chana; Lev, Dorit; Lerman-Sagie, Tally

2011-01-01

156

Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith–Magenis syndrome minimum deletion to ~650 kb  

Microsoft Academic Search

Smith–Magenis syndrome (SMS) is a multiple congenital anomaly\\/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in

Jacqueline Schoumans; Johan Staaf; Göran Jönsson; Johanna Rantala; Kerstin Sars Zimmer; Åke Borg; Magnus Nordenskjöld; Britt-Marie Anderlid

2005-01-01

157

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

158

Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA)  

PubMed Central

Background COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown. Case presentations We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone. Conclusion Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.

2013-01-01

159

mtDNA Deletion in an Iranian Infant with Pearson Marrow Syndrome  

PubMed Central

Background Pearson syndrome (PS) is a rare multisystem mitochondrial disorder of hematopoietic system, characterized by refractory sideroblastic anemia, pancytopenia, exocrine pancreatic insufficiency, and variable neurologic, hepatic, renal, and endocrine failure. Case Presentation We describe a six-month-old female infant with Pearson marrow syndrome who presented with neurological manifestations. She had several episodes of seizures. Hematopoietic abnormalities were macrocytic anemia and neutropenia. Bone marrow aspiration revealed a cellular marrow with marked vacuolization of erythroid and myeloid precursors. Analysis of mtDNA in peripheral blood showed 8.5 kb deletion that was compatible with the diagnosis of PS. Conclusion PS should be considered in infants with neurologic diseases, in patients with cytopenias, and also in patients with acidosis or refractory anemia.

Arzanian, Mohammad Taghi; Eghbali, Aziz; Karimzade, Parvaneh; Ahmadi, Mitra; Houshmand, Massoud; Rezaei, Nima

2010-01-01

160

Exclusion of 22q11 deletion in Noonan syndrome with Tetralogy of Fallot  

SciTech Connect

We read with interest the report of Robin et al. [1995] published in recent issue of the Journal. The authors described 6 patients with Noonan syndrome (NS) who underwent molecular evaluation for submicroscopic deletion of chromosome band 22q11. None of those patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only one patient. This patient had NS-like manifestations without clinical manifestations of DiGeorge (DG) or velo-cardio-facial (VCF) syndromes. The molecular results obtained in the other 5 patients led the authors to conclude that classical NS is not due to del(22)(q11), even if some patients with del(22)(q11) may present NS-like manifestations. 12 refs., 1 tab.

Digilio, M.C.; Marino, B.; Giannotti, A. [Bambino Gesu Hospital, Rome (Italy); Dallapiccola, B. [Univ. of Tor Vergata, Rome (Italy)]|[Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo (Italy)

1996-04-24

161

Syndromic non-compaction of the left ventricle: associated chromosomal anomalies.  

PubMed

Non-compaction of the left ventricle (NCLV) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Associated extracardiac anomalies occur in 14-66% of patients of different series, while chromosomal anomalies were reported in sporadic cases. We investigated the prevalence of chromosomal imbalances in 25 syndromic patients with NCLV, using standard cytogenetic, subtelomeric fluorescent in situ hybridization, and array-comparative genomic hybridization (CGH) analyses. Standard chromosome analysis disclosed an abnormality in three (12%) patients, including a 45,X/46,XX mosaic, a 45,X/46,X,i(Y)(p11) mosaic, and a de novo Robertsonian 13;14 translocation in a child affected by hypomelanosis of Ito. Cryptic chromosome anomalies were found in six (24%) cases, including 1p36 deletion in two patients, 7p14.3p14.1 deletion, 18p subtelomeric deletion, 22q11.2 deletion associated with velo-cardio-facial syndrome, and distal 22q11.2 deletion, each in one case. These results recommend accurate clinical evaluation of patients with NCLV, and suggest that chromosome anomalies occur in about one third of syndromic NCLV individuals, without metabolic/neuromuscular disorder. Array-CGH analysis should be included in the diagnostic protocol of these patients, because different submicroscopic imbalances are causally associated with this disorder and can pinpoint candidate genes for this cardiomyopathy. PMID:23210894

Digilio, M C; Bernardini, L; Gagliardi, M G; Versacci, P; Baban, A; Capolino, R; Dentici, M L; Roberti, M C; Angioni, A; Novelli, A; Marino, B; Dallapiccola, B

2013-10-01

162

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.  

PubMed

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. PMID:23837913

Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

2014-06-01

163

Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome.  

PubMed

Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion. A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity. The majority of the pathogenic sequence changes were found to predict premature protein termination, however, four novel missense changes in the LIS1 homology motif at the 5' end of the gene were identified. The partial gene deletions of different sizes represent ~5.2% of all the pathogenic TCOF1 mutations identified, indicating that gene rearrangements account for a significant proportion of TCS cases. This is the first report of gene rearrangements resulting in TCS. These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis, a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected. PMID:22317976

Bowman, Michael; Oldridge, Michael; Archer, Caroline; O'Rourke, Anthony; McParland, Joanna; Brekelmans, Roel; Seller, Anneke; Lester, Tracy

2012-07-01

164

Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome  

SciTech Connect

The 5q syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensemblgene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34 cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.

Boultwood, Jacqueline; Fidler, Carrie; Strickson, Amanda J.; Watkins, Fiona; Gama, Susana; Kearney, Lyndal; Tosi, Sabrina; Kasprzyk, Arek; Cheng, Jan-Fang; Jaju, Rina J.; Wainscoat, James S.

2002-01-15

165

Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature.  

PubMed

The proximal chromosome 11p contiguous gene deletion syndrome (P11pDS), also known as Potocki-Shaffer syndrome (PSS) or DEFECT 11 (OMIM 601224), is a disorder associated with foramina parietalia permagna and multiple osteochondroma (exostoses). Additional features include mental retardation, craniofacial anomalies, seizures and genitourinary abnormalities. Here, clinico-pathological findings of a unique patient with all of these features and, additionally, enlarged ventricles, hypertrophic obstructive cardiomyopathy and adipositas are described. The brain showed malformative lesions with hallmarks of disturbed bulk growth including micrencephaly, periventricular nodular heterotopias and focal cortical dysplasia in the nodulus of the cerebellar vermis. In addition, symmetric foci with vacuolation of the underlying neuropil, intermingled macrophages and large bizarre, partially vacuolated, reactive astrocytes were found. The proximal short arm of chromosome 11 harbors several candidate genes that could explain the patient's signs and symptoms including ALX4 and EXT2, which are always present in the interstitial deletion of the short arm of chromosome 11 in PSS. In addition, MYBPC3 would be a good candidate for the hypertrophic cardiomyopathy. Furthermore, adipositas might be related to the MAPK8IP1 gene. To the best of our knowledge, the present patient is the oldest one so far described with PSS phenotype and the only case that has undergone detailed neuropathological investigation. PMID:17290930

Romeike, B F M; Wuyts, W

2007-01-01

166

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13. 3  

SciTech Connect

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective confirmation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome. 32 refs., 2 figs.

Breuning, M.H.; Dauwerse, H.G.; Fugazza, G.; Saris, J.J.; Spruit, L.; Winjnen, H.; Beverstock, G.C.; Ommen, G.J.B. van (Leiden Univ. (Netherlands)); Tommerup, N. (John F. Kennedy Inst., Glostrup (Denmark) Avd. for Medisinsk Genetikk, Oslo (Norway)); Hagen, C.B. van der (John F. Kennedy Inst., Glostrup (Denmark)); Imaizumi, Kiyoshi; Kuroki, Yoshikazu (Kanagawa Children's Medical Center, Yokohama (Japan)); Boogaard, M.J. van den; Pater, J.M. de; Hennekam, R.C.M. (Clinical Genetics Center, Utrecht (Netherlands)); Mariman, E.C.M.; Hamel, B.C.J. (University Hospital, Nijmegen (Netherlands)); Himmelbauer, H.; Frischauf, A.M. (Imperial Cancer Research Fund Laboratories, London (United Kingdom)); Stallings, R.L. (Los Alamos National Lab., NM (United States))

1993-02-01

167

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome.  

PubMed

Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ~139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. PMID:21897445

Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K

2012-02-01

168

Deletion at chromosome 16p13. 3 as a cause of Rubinstein-Taybi syndrome: Clinical aspects  

Microsoft Academic Search

In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16p13.3 is described. The authors investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental

R. C. M. Hennekam; M. Tilanus; M. J. H. van den Boogaard; B. C. J. Hamel; H. Voshart-van Heeren; E. C. M. Mariman; S. E. C. van Beersum; M. H. Breuning

1993-01-01

169

Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family.  

PubMed

We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed. PMID:23565415

Madhu, Sri Venkat; Kant, Saket; Holla, Vikram Venkappayya; Arora, Rakesh; Rathi, Sahaj

2012-12-01

170

Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family  

PubMed Central

We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed

Madhu, Sri Venkat; Kant, Saket; Holla, Vikram Venkappayya; Arora, Rakesh; Rathi, Sahaj

2012-01-01

171

16p Subtelomeric Duplication with Vascular Anomalies: an Albanian Case Report and Literature Review  

PubMed Central

A patient with karyotype 46,XY,der(4) was recognized by standard cytogenetic techniques, and presented with facial features, neurological impairment and pulmonary hypertension. Multiplex ligation-dependent probe amplification (MLPA) demonstrated duplication of the subtelomeric region of chromosome 16p and deletion of the subtelomeric region of chromosome 4q, suggesting a translocation between 4q and 16p. The karyotype of his parents was normal and their MLPA analysis also indicated a de novo imbalance. He had microcephaly, high frontal hairline, thin blond hair, bilateral blepharophimosis and palpebral ptosis, short nose, everted upper lip, cleft palate, micrognathia, cupped anteverted ears, hypoplastic distal phalanges and bilateral inguinal hernia. He also had pulmonary hypertension with tricuspidal regurgitation; cavernous liver hemangioma anomalies have been previously described in association with dup16p. We concluded that pulmonary and other vascular anomalies can be a feature of dup16p. We believe this is the first confirmed case of a 16p subtelomeric duplication with vascular anomalies identified in Albania.

Babameto-Laku, A; Mokini, V; Kuneshka, N; Sallabanda, S; Ylli, Z

2012-01-01

172

Respiratory failure, cleft palate and epilepsy in the mouse model of human Xq22.1 deletion syndrome.  

PubMed

Chromosomal segmental deletion is a frequent cause of human diseases. A familial 1.1 Mb deletion of human chromosome Xq22.1 associates with epilepsy, cleft palate and developmental defects in heterozygous female patients. Here, we describe a mouse mutant with a targeted deletion of the syntenic segment of the mouse X chromosome that phenocopies the human syndrome. Male mice with a deletion of a 1.1 Mb Nxf2-Nxf3 X-chromosomal segment exhibit respiratory failure, neonatal lethality and cleft palate. In female mice, heterozygosity for the deletion manifests cleft palate, early postnatal lethality, postnatal growth delay and spontaneous seizures in surviving animals, apparently due to X-chromosome inactivation. Furthermore, loss of a 0.35 Mb subregion containing Armcx5, Gprasp1, Gprasp2 and Bhlhb9 is sufficient to cause the Xq22.1 syndrome phenotype. Our results support that the 1.1 Mb deletion of human Xq22.1 is the genetic cause of the associated syndrome. PMID:24569167

Zhou, Jian; Goldberg, Ethan M; Leu, N Adrian; Zhou, Lei; Coulter, Douglas A; Wang, P Jeremy

2014-07-15

173

Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome.  

PubMed

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. Schizotypy was assessed with the Kings Schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy. PMID:24534796

Monks, Stephen; Niarchou, Maria; Davies, Aimée R; Walters, James T R; Williams, Nigel; Owen, Michael J; van den Bree, Marianne B M; Murphy, Kieran C

2014-03-01

174

Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.  

PubMed

3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2-3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development. PMID:15106122

Fernandez, Thomas; Morgan, Thomas; Davis, Nicole; Klin, Ami; Morris, Ashley; Farhi, Anita; Lifton, Richard P; State, Matthew W

2004-06-01

175

Reciprocal Deletion and Duplication of 17p11.2-11.2: Korean Patients with Smith-Magenis Syndrome and Potocki-Lupski Syndrome  

PubMed Central

Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1 (Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features, aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mb-sized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF.

Lee, Cha Gon; Park, Sang-Jin; Yun, Jun-No; Yim, Shin-Young

2012-01-01

176

Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome.  

PubMed

Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1 (Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features, aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mb-sized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF. PMID:23255863

Lee, Cha Gon; Park, Sang-Jin; Yun, Jun-No; Yim, Shin-Young; Sohn, Young Bae

2012-12-01

177

How to diagnose the 22q11.2 deletion syndrome in patients with schizophrenia: a case report  

PubMed Central

The 22q11.2 deletion syndrome is caused by a microdeletion of chromosome 22. One third of all patients with 22q11.2 deletion develop schizophrenia-like symptoms. In general, the prevalence of 22q11.2 deletion in patients with schizophrenia is 1%–2%. The 22q11.2 deletion is one of the major known genetic risk factors for schizophrenia. However, clinical differences in the phenotypes between patients with schizophrenia who are 22q11.2 deletion carriers and those who are not are still unknown. Therefore, it may be difficult to diagnose 22q11.2 deletion in patients with schizophrenia on the basis of clinical symptoms. To date, only two Japanese patients with the deletion have been identified through microdeletion studies of patients with schizophrenia in the Japanese population. Herein, we report the case study of a 48-year-old Japanese woman with 22q11.2 deletion who had a 30-year history of schizophrenia. Based on craniofacial anomalies, unpredictable agitation, hypocalcemia, and brain imaging finding, we suspected the 22q11.2 deletion in clinical populations and diagnosed the deletion using fluorescence in situ hybridization analysis. To find common phenotypes in Japanese patients with the deletion who have schizophrenia-like symptoms, we compared phenotypes among three Japanese cases. The common phenotypes were an absence of congenital cardiovascular anomalies and the presence of current findings of low intellectual ability, agitation, and hypocalcemia. We propose that hypocalcemia and agitation in patients with schizophrenia may derive from the 22q11.2 deletion, particularly when these phenotypes are coupled with schizophrenia-like symptoms.

2013-01-01

178

Typical Renal-coloboma Syndrome Phenotype in a Patient with a Submicroscopic Deletion of the PAX2 Gene  

PubMed Central

We present a patient with optic nerve hypoplasia, secondary strabismus, mild deafness, abnormal external ear helices and renal hypoplasia. The clinical phenotype was consistent with renal-coloboma syndrome, but no point mutation in the PAX2 gene could be identified. High resolution array Comparative Genomic Hybridization (aCGH) analysis showed that this patient has a submicroscopic deletion on chromosome 10, affecting the entire coding region of the PAX2 gene. This finding provided the molecular confirmation of the patient’s clinical diagnosis and showed that, in addition to point mutations, deletions of the PAX2 gene contribute to the etiology of the renal-coloboma syndrome.

Laimutis, Kucinskas; Jackson, Craig; Xu, Xinjie; Warman, Berta; Sarunas, Rudaitis; Birute, Pundziene; Schimmenti, Lisa A.; Raca, Gordana

2012-01-01

179

[A case in which chromosome 5q deletion syndrome resistant to lenalidomide therapy transformed to refractory anemia with excess blasts].  

PubMed

An 80-year-old man was admitted to our hospital because of pancytopenia. Bone marrow examination revealed an increase in the number of dysplastic cells indicating trilineage dysplasia. A 5q13q31 deletion was the only genetic abnormality found, and consequently, 5q deletion syndrome was diagnosed. Although lenalidomide therapy was initiated, it had to be discontinued because of Stevens-Johnson syndrome, which occurred during the second course of treatment. There was no discernible hematological improvement, and bone marrow aspiration showed transformation to refractory anemia with excess blasts-2(RAEB-2)after lenalidomide therapy. However, by changing the therapy to azacitidine, cytogenetic remission was achieved. PMID:24335378

Yamada, Michiko; Kuroda, Hiroyuki; Jomen, Wataru; Yoshida, Masahiro; Miura, Shogo; Abe, Tomoyuki; Sakurai, Tamaki; Fujii, Shigeyuki; Maeda, Masahiro; Fujita, Miri; Nagashima, Kazuo; Arihara, Yohei; Hirako, Tasuku; Kato, Junji

2013-12-01

180

Monosomy 1p36 - a multifaceted and still enigmatic syndrome: four clinically diverse cases with shared white matter abnormalities.  

PubMed

Monosomy 1p36 is the most common subtelomeric deletion syndrome seen in humans. Uniform features of the syndrome include early developmental delay and consequent intellectual disability, muscular hypotonia, and characteristic dysmorphic facial features. The gene-rich nature of the chromosomal band, inconsistent deletion sizes and overlapping clinical features have complicated relevant genotype-phenotype correlations. We describe four patients with isolated chromosome 1p36 deletions. All patients shared white matter abnormalities, allowing us to narrow the critical region for white matter involvement to the deletion size of up to 2.5 Mb from the telomere. We hypothesise that there might be a gene(s) responsible for myelin development in the 1p36 subtelomeric region. Other significant clinical findings were progressive spastic paraparesis, epileptic encephalopathy, various skeletal anomalies, Prader-Willi-like phenotype, neoplastic changes - a haemangioma and a benign skin tumour, and in one case, sleep myoclonus, a clinical entity not previously described in association with 1p36 monosomy. Combined with prior studies, our results suggest that the clinical features seen in monosomy 1p36 have more complex causes than a classical contiguous gene deletion syndrome. PMID:24529875

Õiglane-Shlik, Eve; Puusepp, Sanna; Talvik, Inga; Vaher, Ulvi; Rein, Reet; Tammur, Pille; Reimand, Tiia; Teek, Rita; Žilina, Olga; Tomberg, Tiiu; Õunap, Katrin

2014-05-01

181

An atypical case of fragile X syndrome caused by a deletion that includes the FMR-1 gene  

SciTech Connect

Fragile X syndrome results from the transcriptional inactivation of the FMR-1 gene. This is commonly caused by the expansion of an unstable CGG trinucleotide repeat in the first exon of the FMR-1 gene. We describe here an atypical case of fragile X syndrome caused by a deletion that includes the FMR-1 gene. RK is a 6-year-old hyperactive, mentally retarded male. Southern analysis of PstI digested genomic DNA was performed using a 558 bp XhoI-PstI fragment specific for the 5`-end of the FMR-1 gene. This analysis revealed the absence of the normal 1.0 kb PstI fragment, indicating the deletion of at least a portion of the FMR-1 gene. PCR analysis using Xq27.3 microsatellite and STS markers confirmed the presence of a deletion of at least 600 kb encompassing the FMR-1 gene. Southern blot and PCR analysis demonstrated that this deletion was maternally transmitted and arose as a new mutation on the grandpaternal X-chromosome. High resolution chromosome banding revealed an extremely small deletion of a portion of band Xq27 which was confirmed by fluorescent in situ hybridrization (FISH) analysis using a 34 kb cosmid containing the FMR-1 gene. As expected, RK manifests physical features typical of fragile X syndrome, including a high arched palate, prognathism, and large ears. Interestingly, RK also presents with anal atresia, obesity and short stature, features not part of fragile X syndrome. In addition, RK has normal sized testicles and does not exhibit the characteristic gaze avoidance, hand-flapping, and crowd anxiety behaviors. These atypical features may result from the deletion of additional genes in the vicinity of the FMR-1 gene. Further work is underway to determine more precisely the extent of the deletion in RK`s DNA.

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

1994-09-01

182

CHARGE Syndrome and Chromosome 22q11.2 Deletion Syndrome: A Comparison of Immunologic and Non-Immunologic Phenotypic Features  

PubMed Central

Objectives CHARGE syndrome and chromosome 22q11.2 deletion syndrome are known to have significant clinical overlap including cardiac anomalies, ear abnormalities, hearing loss, developmental delay, renal abnormalities, hearing loss, and cleft palate. Immunodeficiency has been well documented in 22q11.2 deletion, but there is limited recognition of this potentially serious complication in CHARGE syndrome. The goals of our study were to identify clinical features unique to CHARGE syndrome or 22q11.2 deletion and to describe the spectrum of immune deficiency found in CHARGE patients. Methods This study includes 25 children diagnosed with CHARGE syndrome with positive CHD7 mutations, through the Children’s Hospital of Philadelphia genetics program. Clinical features and laboratory findings were reviewed retrospectively. We compared our findings to data available for a large cohort of 22q11.2 deletion syndrome patients followed in our clinical genetics program. Results Features found more commonly in CHARGE syndrome included coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, and genital hypoplasia in males. A high incidence of marked hypocalcemia was observed in our study group (72%). We found a spectrum of cell-mediated immune deficiency in our study group, which ranged from lymphopenia (60%) to severe-combined immune deficiency (8%). Defects in humoral immunity were documented in 4 patients and included severe hypogammaglobulinemia with decreased T-cell numbers, transient hypogammaglobulinemia during infancy, and IgA deficiency. Conclusion The presence of coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, or genital hypoplasia in males should alert the clinician to the possibility of CHARGE syndrome rather than the 22q11.2 deletion. Molecular testing for CHD7 mutations may help to confirm the diagnosis. In this study, significant hypocalcemia and lymphopenia occurred more frequently in CHARGE syndrome patients than in 22q11.2 deletion syndrome patients. Early inclusion of immunologists to the multi-disciplinary care team (as with 22q11.2 deletion) may be of great benefit to affected patients.

Jyonouchi, Soma; McDonald-McGinn, Donna M.; Bale, Sherri; Zackai, Elaine H.; Sullivan, Kathleen E.

2014-01-01

183

Lack of transmission of deleted mtDNA from a woman with Kearns-Sayre syndrome to her child.  

PubMed Central

We have investigated the daughter of a woman with Kearns-Sayre syndrome. The woman had a high percentage of deleted mtDNA in muscle, but no deleted mtDNA was detected in fibroblasts, bone marrow, and peripheral blood cells by Southern blot analysis. With PCR, analytical sensitivity was significantly increased, and deleted mtDNA was detected in all examined tissues from this patient. The patient had healthy parents and nine healthy siblings. No deleted mtDNA was detected in blood from the mother of the patient. The patient had an uneventful pregnancy and delivered at term. Deleted mtDNA could not be detected in placenta by Southern blot analysis. With PCR, deleted mtDNA was detected in the majority of placental specimens. This finding may, however, be due to contamination with maternal DNA. The patient's daughter was healthy at age 5 mo, and morphologic examination of muscle was normal. No transmission of deleted mtDNA to the daughter could be detected by Southern blot and PCR analysis of peripheral blood cells, bone marrow, fibroblasts, and muscle. The presence of deleted mtDNA was excluded at a fractional level of less than 1:100,000 in all examined tissues from the daughter. Images Figure 1 Figure 2

Larsson, N G; Eiken, H G; Boman, H; Holme, E; Oldfors, A; Tulinius, M H

1992-01-01

184

RAI1 is a novel polyglutamine encoding gene that is deleted in Smith–Magenis syndrome patients  

Microsoft Academic Search

The human chromosomal band 17p11.2 is a genetically unstable interval. It has been shown to be deleted in patients suffering from Smith–Magenis syndrome. Previous efforts of physical and transcriptional mapping in 17p11.2 and subsequent genomic sequencing of the candidate interval allowed the identification of new genes that might be responsible for the Smith–Magenis syndrome. In this report, one of these

Peter Seranski; Céline Hoff; Uwe Radelof; Steffen Hennig; Richard Reinhardt; Charles E Schwartz; Nina S Heiss; Annemarie Poustka

2001-01-01

185

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

186

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

187

Children with chromosome 22q11.2 deletion syndrome exhibit impaired spatial working memory.  

PubMed

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 22q11.2DS (n ?=? 47) and typically developing controls (n ?=? 49) ages 6-15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance. PMID:24679349

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

2014-03-01

188

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

PubMed Central

Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. We 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 22q11.2DS (n = 47) and typically developing controls (n = 49) ages 6–15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance.

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

2014-01-01

189

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

PubMed Central

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11-q13. Approximately 70% of these patients have a large deletion of approximately 4 Mb extending from D15S9 (ML34) through D15S12 (IR10). 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 from 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. Images Figure 2

Christian, S L; Robinson, W P; Huang, B; Mutirangura, A; Line, M R; Nakao, M; Surti, U; Chakravarti, A; Ledbetter, D H

1995-01-01

190

Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome.  

PubMed

We report on an infant with Robin sequence; mild developmental delay; a left ulnar ray defect with absent ulna and associated metacarpals, carpals and phalanges; and a right ulnar nerve hypoplasia. He had a de novo interstitial deletion of 4q32-->q34. The critical region involved in the 4q terminal deletion syndrome may be 4q33. This conclusion was suggested by showing that del(4)(q31qter), del(4)(q32qter), and del(4)(q33qter) result in a similarly severe phenotype. In addition, we propose that genes for distal arm development, in particular for development of the left ulnar ray, central nervous system development, and cleft lip and palate, may be located at 4q33. PMID:11241465

Keeling, S L; Lee-Jones, L; Thompson, P

2001-03-01

191

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

192

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.

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

2011-01-01

193

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

194

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

195

Emotion Regulation and Development in Children with Autism and 22q13 Deletion Syndrome: Evidence for Group Differences  

ERIC Educational Resources Information Center

Emotion regulation (ER) abilities and developmental differences were investigated among 19 children with autism and 18 children with 22q13 Deletion Syndrome (a rare chromosomal disorder with certain autistic symptoms). The purpose of this study was to examine the phenotypic similarities between the two disorders. ER was measured by the Temperament…

Glaser, Sarah E.; Shaw, Steven R.

2011-01-01

196

Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene  

Microsoft Academic Search

We report on the clinical and molecular characterization of 3 sibs with X-linked ichthyosis and variable expression of Kallmann syndrome. One of the affected brothers had mild hyposmia and showed normal pubertal progression. However, we demonstrated the same partial deletion of the X-linked Kallmann gene, sparing the first exon in the mildly affected patient as well as in one of

Giancarlo Parenti; Maria Grazia Rizzolo; Monica Ghezzi; Salvatore Di Maio; Maria Pia Sperandeo; Barbara Incerti; Brunella Franco; Andrea Ballabio; Generoso Andria

1995-01-01

197

Small Deletions of SATB2 Cause Some of the Clinical Features of the 2q33.1 Microdeletion Syndrome  

PubMed Central

Recurrent deletions of 2q32q33 have recently been reported as a new microdeletion syndrome. Clinical features of this syndrome include severe mental retardation, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties and cleft or high palate. The commonly deleted region contains at least seven genes. Haploinsufficiency of one of these genes, SATB2, a DNA-binding protein that regulates gene expression, has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome. In this study we describe three individuals with smaller microdeletions of this region, within 2q33.1. The deletions ranged in size from 173.1 kb to 185.2 kb and spanned part of SATB2. Review of clinical records showed similar clinical features among these individuals, including severe developmental delay and tooth abnormalities. Two of the individuals had behavioral problems. Only one of the subjects presented here had a cleft palate, suggesting reduced penetrance for this feature. Our results suggest that deletion of SATB2 is responsible for several of the clinical features associated with 2q32q33 microdeletion syndrome.

Rosenfeld, Jill A.; Ballif, Blake C.; Lucas, Ann; Spence, Edward J.; Powell, Cynthia; Aylsworth, Arthur S.; Torchia, Beth A.; Shaffer, Lisa G.

2009-01-01

198

A Turkish patient with large 17p11.2 deletion presenting with Smith Magenis syndrome.  

PubMed

Smith-Magenis syndrome (SMS), which occurs as a result of an interstitial deletion within chromosome 17p11.2-p12, is a disorder that presents itself with minor dysmorphic features, brachydactyly, short stature, hypotonia, delayed speech, cognitive deficits and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behavior. We present a girl with full SMS phenotype. G-banding cytogenetic analysis showed normal 46,XX karyotype. Whole-genome array comparative genomic hybridization (CGH) was performed due to the severity of the phenotype and the unusual features present in the patient. An interstitial deletion in 17p11.2-p12, approximately 4.73 Mb in size was determined. Characteristic physical and behavioral phenotype strongly suggested SMS. This, to the best of our knowledge is the first patient with SMS reported in Turkey. We emphasize the need for whole genome analysis in multiple congenital abnormalities/mental retardation disorders with unusual and severe phenotypes. PMID:21614983

Tug, E; Cine, N; Aydin, H

2011-01-01

199

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome  

PubMed Central

Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage—the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)—specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement.

Meechan, Daniel W.; Tucker, Eric S.; Maynard, Thomas M.; LaMantia, Anthony-Samuel

2012-01-01

200

Isolation of expressed sequences from the region commonly deleted in Velo-cardio-facial syndrome  

SciTech Connect

Velo-cardio-facial syndrome (VCFS) is a relatively common autosomal dominant genetic disorder characterized by cleft palate, cardiac abnormalities, learning disabilities and a characteristic facial dysmorphology. Most VCFS patients have interstitial deletions of 22q11 of 1-2 mb. In an effort to isolate the gene(s) responsible for VCFS we have utilized a hybrid selection protocol to recover expressed sequences from three non-overlapping YACs comprising almost 1 mb of the commonly deleted region. Total yeast genomic DNA or isolated YAC DNA was immobilized on Hybond-N filters, blocked with yeast and human ribosomal and human repetitive sequences and hybridized with a mixture of random primed short fragment cDNA libraries. Six human short fragment libraries derived from total fetus, fetal brain, adult brain, testes, thymus and spleen have been used for the selections. Short fragment cDNAs retained on the filter were passed through a second round of selection and cloned into lambda gt10. cDNAs shown to originate from the YACs and from chromosome 22 are being used to isolate full length cDNAs. Three genes known to be present on these YACs, catechol-O-methyltransferase, tuple 1 and clathrin heavy chain have been recovered. Additionally, a gene related to the murine p120 gene and a number of novel short cDNAs have been isolated. The role of these genes in VCFS is being investigated.

Sirotkin, H.; Morrow, B.; DasGupta, R. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others

1994-09-01

201

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene.  

PubMed

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype. PMID:24372652

Ishida-Yamamoto, Akemi; Furio, Laetitia; Igawa, Satomi; Honma, Masaru; Tron, Elodie; Malan, Valerie; Murakami, Masamoto; Hovnanian, Alain

2014-01-01

202

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.

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

203

Physical map and cosmid contig encompassing a new interstitial deletion of the X-linked lymphoproliferative syndrome region.  

PubMed

The X-linked lymphoproliferative syndrome (XLP) is an inherited immuno-deficiency to Epstein-Barr virus infection that has been mapped to chromosome Xq25. Molecular analysis of XLP patients from ten different families identified a small interstitial constitutional deletion in 1 patient (XLP-D). This deletion, initially defined by a single marker, DF83, known to map to interval Xq24-q26.1, is nested within a previously reported and much larger deletion in another XLP patient (XLP-739). A cosmid minilibrary was constructed from a single mega-YAC and used to establish a contig encompassing the whole XLP-D deletion and a portion of the XLP-739 deletion. Based on this contig, the size of the XLP-D deletion can be estimated at 130 kb. The identification of this minimal deletion, within which at least a portion of the XLP gene is likely to reside, should greatly facilitate efforts in isolating the gene. PMID:9043868

Lamartine, J; Nichols, K E; Yin, L; Krainer, M; Heitzmann, F; Bernard, A; Gaudi, S; Lenoir, G M; Sullivan, J L; Ikeda, J E; Porta, G; Schlessinger, D; Romeo, G; Haber, D A; Sylla, B S; Harkin, D P

1996-01-01

204

Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene.  

PubMed

Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia. PMID:24056535

Conti, Valerio; Carabalona, Aurelie; Pallesi-Pocachard, Emilie; Parrini, Elena; Leventer, Richard J; Buhler, Emmanuelle; McGillivray, George; Michel, François J; Striano, Pasquale; Mei, Davide; Watrin, Françoise; Lise, Stefano; Pagnamenta, Alistair T; Taylor, Jenny C; Kini, Usha; Clayton-Smith, Jill; Novara, Francesca; Zuffardi, Orsetta; Dobyns, William B; Scheffer, Ingrid E; Robertson, Stephen P; Berkovic, Samuel F; Represa, Alfonso; Keays, David A; Cardoso, Carlos; Guerrini, Renzo

2013-11-01

205

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

206

Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR.  

PubMed

Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome characterized by facial abnormalities, broad thumbs, broad big toes, and growth and mental retardation as the main clinical features. RTS was shown to be associated with disruption of the CREB-binding protein gene CBP (CREBBP), either by gross chromosomal rearrangements or by point mutations. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (about 10%). Most deletion studies in RTS are performed by FISH analysis, and five cosmids must be used to cover the whole of the CBP gene, which spreads over 150 kb. Here we report the design of gene dosage assays by real-time quantitative PCR that are targeted on three exons located respectively at the 5' end (exon 2), in the middle (exon 12), and at the 3' end (exon 30) of the CBP gene. This technique proved to be efficient and powerful in finding deletions and complementary to the other available techniques, since it allowed us to identify deletions at the 3' end of the gene that had been missed by FISH analysis, and to refine some deletion breakpoints. Our results therefore suggest that real-time quantitative PCR is a useful technique to be included in the deletion search in RTS patients. PMID:14974086

Coupry, Isabelle; Monnet, Laurence; Attia, Azza Abd El Moneim; Taine, Laurence; Lacombe, Didier; Arveiler, Benoît

2004-03-01

207

Detection of 22q11.2 deletion among 139 patients with Di George/Velocardiofacial syndrome features.  

PubMed

Cytogenetic and FISH analysis was performed in 139 patients to detect the pathognomonic of Di George/ Velocardiofacial syndrome (DGS/VFCS) deletion 22q11.2. An abnormal karyotype was revealed in 2/139 cases (47, XXY and 46, XX, 2p+). A deletion was found in 17/139 (12.2%) patients (14 males/ 3 females), inherited in 3 (2 maternal and 1 paternal). Patients with 22q11.2 deletion exhibited facial dysmorphic features (82%), congenital heart defects (70%), immunological problems (47%), multiple congenital anomalies (64%), hypocalcemia (47%), mental retardation/learning difficulties (35%), cleft palate/velopharyngeal insufficiency (23.5%), seizures/hypotonia (23%) and growth retardation (12%). Among 56/139 patients with detailed available clinical data, the 22q11.2 deletion was confirmed in all cases with hypocalcemia and in over half of the cases with multiple congenital anomalies, immunological problems and hypotonia/seizures (70%, 60% and 57%, respectively). Genetic reevaluation of 39 patients without the 22q11.2 deletion contributed to the classification of 14 (37%) under different syndromes, emphasizing the need for stricter referral criteria. PMID:15523900

Kitsiou-Tzeli, S; Kolialexi, A; Fryssira, H; Galla-Voumvouraki, A; Salavoura, K; Kanariou, M; Tsangaris, G Th; Kanavakis, E; Mavrou, A

2004-01-01

208

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

SciTech Connect

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 non-informative) 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. 53 refs., 5 figs., 2 tabs.

Perez Jurado, L.A.; Peoples, R.; Francke, U. [Stanford Univ. School of Medicine, CA (United States)] [and others

1996-10-01

209

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion  

PubMed Central

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

Duraturo, Francesca; Cavallo, Angela; Liccardo, Raffaella; Cudia, Bianca; De Rosa, Marina; Diana, Giuseppe; Izzo, Paola

2013-01-01

210

Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome.  

PubMed

HPC-1/syntaxin 1A is a membrane protein that plays an important role in exocytosis of neurotransmitters from neuronal cells. We previously mapped the human HPC-1/syntaxin 1A gene (STX1A) to chromosome 7q11.2, which is within the Williams syndrome (WS) region. Here, we performed FISH analysis on 46 patients with WS to examine the relationship between STX1A and WS. Our results showed a hemizygous deletion of the HPC-1/syntaxin 1A gene in each patient, suggesting that the neurological symptoms of WS may be related to the hemizygous deletion of STX1A. PMID:9763659

Nakayama, T; Matsuoka, R; Kimura, M; Hirota, H; Mikoshiba, K; Shimizu, Y; Shimizu, N; Akagawa, K

1998-01-01

211

Socioeconomic Status and Psychological Function in Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Genetic Counseling  

Microsoft Academic Search

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition\\u000a and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes\\u000a in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the\\u000a environment in either mitigating or contributing to

Vandana Shashi; Matcheri Keshavan; Jessica Kaczorowski; Kelly Schoch; Kathryn E. Lewandowski; Allyn McConkie-Rosell; Stephen R. Hooper; Thomas R. Kwapil

2010-01-01

212

Presenting symptoms in adults with the 22q11 deletion syndrome.  

PubMed

A definitive molecular diagnosis of 22q11 Deletion Syndrome (22q11DS) even if occurring later in life, has important genetic, medical and emotional impact on the patients and their families. The aim of this study is to describe presenting symptoms and age at diagnosis in an adult 22q11DS population. A retrospective study was performed on 65 individuals diagnosed with 22q11DS at adult age. Data were collected on adults referred to the genetic clinic or actively recruited through systematic diagnostic examination in both institutions and a psychiatric unit for intellectually disabled. Presenting symptoms were categorized into seven groups: familial occurrence, intellectual disability, cardiac anomalies, palatal anomalies, facial dysmorphic features, psychiatric problems and 'other' (comprising all other features associated with 22q11DS). Age at diagnosis was defined as the age at which the 22q11.2 deletion was detected by fluorescence in situ hybridization or comparative genomic hybridization. Ascertainment subgroups were different in presenting symptoms and age at diagnosis. Adults were referred to the genetic clinic mainly because of familial occurrence, cardiac defects and psychiatric disorders whereas adults diagnosed in institutions for intellectually disabled presented mainly with moderate to severe intellectual disability and psychotic disorders. Adults diagnosed at the psychiatric unit for intellectually disabled had a variety of psychiatric disorders but none of them had additional physical features. This emphasizes the need to stay alert for presenting symptoms such as conotruncal heart defects or moderate to severe intellectual disability in combination with a history of psychiatric disorders, even in the absence of obvious physical features. PMID:24576609

Vogels, Annick; Schevenels, Sara; Cayenberghs, Richard; Weyts, Eddy; Van Buggenhout, Griet; Swillen, Ann; Van Esch, Hilde; de Ravel, Thomy; Corveleyn, Pieter; Devriendt, Koen

2014-03-01

213

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.

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

2014-01-01

214

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

215

The 13q- syndrome: the molecular definition of a critical deletion region in band 13q32.  

PubMed Central

Patients with interstitial deletions of the long arm of chromosome 13 may have widely varying phenotypes. From cytogenetic analysis, we have postulated that there is a discrete region in 13q32 where deletion leads to a syndrome of severe malformations, including digital and brain anomalies. To test this hypothesis at the molecular level, we have studied the deletions in 17 patients; 5 had severe malformations, while the remaining 12 had only minor malformations. Our results indicate that the deletions in the severely affected patients all involve an overlapping region in q32, while the deletions in the mildly affected patients include some, but not all, of this overlapping region. Our findings are consistent with the hypothesis that the severely malformed 13q- phenotype results from the deletion of a critical region in 13q32. This region is presently defined as lying between D13S136 and D13S147 and is on the order of 1 Mb in size. Images Figure 3 Figure 4

Brown, S; Russo, J; Chitayat, D; Warburton, D

1995-01-01

216

Velo-Cardio-Facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region  

SciTech Connect

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletion has not been reported previously. An accurate diagnosis of the 22q11 deletion is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. 31 refs., 3 figs.

Nickel, R.E.; Pillers, D.M.; Merkens, M.; Magenis, R.E.; Zonana, J. [Oregon Health Sciences Univ., Portland, OR (United States); Driscoll, D.A.; Emanuel, B.S. [Univ. of Pennsylvania Medical Center, Philadelphia, PA (United States)

1994-10-01

217

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

PubMed Central

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' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)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. Images Figure 1 Figure 2 Figure 3

Nickerson, E; Greenberg, F; Keating, M T; McCaskill, C; Shaffer, L G

1995-01-01

218

Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion.  

PubMed

We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(q11-13), spanning markers from D15S9 to D15S12, about 3 center dot 5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11 center dot 2 years (range 3 to 34 years). All patients were ataxic, severely retarded, and lacking recognisable speech. In all patients, head circumference (HC) at birth was normal but skewed in distribution, with 62 center dot 5% at the 10th centile. At last review HC was around the 50th centile in three patients (12 center dot 5%) while 15 had poor postnatal head growth. Short stature was not invariable, 5/26 (19%) were on or above the 50th centile. Hypotonia at birth was recorded in 15/24 (63%) and neonatal feeding difficulties were recorded in 20/26 (77%). Epilepsy was present in 26/27 (96%) with onset by the third year of life in 20 patients (83%). Improvement in epilepsy was reported in 11/16 patients (69%) with age. An abnormal EEG was reported in 25/25 patients. Hypopigmentation was present in 19/26 (73%). One patient had oculocutaneous albinism. Five patients could not walk independently. Of the remaining 22 who could walk, age of onset of walking ranged from 2 to 8 years. Disrupted sleep patterns were present in 18/21 patients (86%), with improvement in 9/12 patients (75%) over 10 years of age. The clinical features in this group of deletional AS patients were similar to previous reports, but these have not separated patients into subgroups based on DNA studies. In our group of deletional cases, 100% showed severe mental retardation, ataxic movements, absent language, abnormal EEG, happy disposition (noted in infancy in 95%), normal birth weight and head circumference at birth, and a large, wide mouth. These features occurred with a higher frequency than in AS patients as a whole. Our study also provided information on the evolution of the phenotype. The data can act as a benchmark for comparisons of AS resulting from other genetic mechanisms. PMID:8929945

Smith, A; Wiles, C; Haan, E; McGill, J; Wallace, G; Dixon, J; Selby, R; Colley, A; Marks, R; Trent, R J

1996-02-01

219

Deficits in Mental State Attributions in Individuals with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome)  

PubMed Central

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 (UCLA and 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 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.

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.

2012-01-01

220

Characteristic Face: A Key Indicator for Direct Diagnosis of 22q11.2 Deletions in Chinese Velocardiofacial Syndrome Patients  

PubMed Central

Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients.

Xu, Chen; Wang, Ke; Wang, Huijun; Zheng, Fengyun; Ma, Duan; Wang, Guomin

2013-01-01

221

A 1.1Mb deletion in distal 13q deletion syndrome region with congenital heart defect and postaxial polydactyly: additional support for a CHD locus at distal 13q34 region.  

PubMed

13q deletion syndrome is a rare genetic disorder, especially for group 3 deletion (13q33-q34 deletion). Previously we described a patient with congenital heart defect and mental retardation and proposed that a distal 6Mb region might contain the causative gene of congenital heart defect. Here we present a new patient with congenital heart defects (CHD), hand and foot anomalies and mild mental retardation. We identified a 1.1Mb deletion at chromosome 13q34 with high resolution SNP-array BeadChips (HumanOmni1-Quad, Illumina, USA). This chromosome region contains ten annotated genes, including GRK1, TFDP1, RASA3 and GAS6. To our knowledge, this represents the smallest 13q34 deletion identified to date. Our study provides additional support that distal 13q34 deletion region might contain key gene(s) responsible for cardiac development. PMID:23639964

Yang, Yi-Feng; Ai, Qi; Huang, Can; Chen, Jin-Lan; Wang, Jian; Xie, Li; Zhang, Wei-Zhi; Yang, Jin-Fu; Tan, Zhi-Ping

2013-10-01

222

Premature death in adults with 22q11.2 deletion syndrome  

PubMed Central

Background 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disease with a prevalence of 1/4000. Variable expression of congenital and later onset features contributes to its under-recognition. Longevity in those surviving childhood is believed to be normal but data are limited. Methods We prospectively followed 264 subjects; 102 adults (>17 years) with 22q11.2DS (44 male (M), 58 female (F); mean (SD) age 33.6 (10.9) years) and their 162 unaffected siblings (77 M, 85 F; mean age 36.1 (12.2) years). We compared survival between groups using Kaplan–Meier estimates. Results Twelve (11.8%; 4 M, 8 F) individuals with 22q11.2DS and no siblings died (p<0.0001). Survival to ages 40 and 50 years was 89.9% and 73.9%, respectively. Median age at death was 41.5 (range 18.1–68.6) years. Deaths included two (7.7%) of 26 subjects with neither major congenital heart disease (CHD) nor schizophrenia. Four of six sudden and unexpected deaths occurred in individuals with no major CHD. There was no evidence of cancer or coronary artery disease or family history of sudden death in the 12 patients who died, six of whom had autopsies. Discussion Individuals with 22q11.2DS who survive childhood have diminished life expectancy and increased risk of sudden death not attributable to any single factor. Some sudden and/or premature deaths observed in the general population may represent undiagnosed 22q11.2DS. Increased recognition of the syndrome by family doctors, specialists and coroners will be essential to facilitate the tissue studies needed to determine underlying mechanisms.

Bassett, A S; Chow, E W C; Husted, J; Hodgkinson, K A; Oechslin, E; Harris, L; Silversides, C

2011-01-01

223

Interstitial deletion 11(p11.12p11.2) and analphoid marker formation results in inherited Potocki-Shaffer syndrome.  

PubMed

We report a family with inherited Potocki-Shaffer syndrome. The phenotypically normal mother has an interstitial deletion of 11(p11.12p11.2) with neocentric marker chromosome formation. The marker chromosome contains the deleted material on 11p11.2 and is likely a ring. The patient inherited a maternal deleted chromosome 11 but not the marker chromosome, thus resulting in an unbalanced karyotype along with the phenotype of Potocki-Shaffer syndrome. The deleted region in our case-11p11.12p11.2-is a newly reported site of constitutional neocentromere formation. This is also the first report describing deletion of 11p11.12-p11.2 and neocentromere formation resulting in inherited Potocki-Shaffer syndrome. PMID:15666301

Chuang, Louise; Wakui, Keiko; Sue, Whey-Chen; Su, Mei-Hsu; Shaffer, Lisa G; Kuo, Pao-Lin

2005-03-01

224

Analysis of 22q11.2 deletions by FISH in a series of velocardiofacial syndrome patients  

SciTech Connect

Deletions in chromosome 22 band q11.2 have been associated with velocardiofacial (VCF or Shprintzen) syndrome and the DiGeorge anomaly. A study of VCF patients evaluated at the UCSF Medical Center was undertaken to correlate disease phenotype with presence or absence of a deletion. Patients referred for this study had at least two of the following: dysmorphic facial features, frequent ear infections or hearing loss, palate abnormalities, thymic hypoplasia, hypocalcemia, congenital heart defect, hypotonia, and growth or language delay. Fluorescence in situ hybridization (FISH) using the DiGeorge critical region probe N25 was used to classify patients according to the presence or absence of a deletion in 22q11.2, and the results were compared to clinical characteristics. We have completed studies on 58 patients with features of VCF. Twenty-one patients (36%) were found to have a deletion in 22q11.2 by FISH. A retrospective study of archived slides from 14 patients originally studied only by prometaphase GTG banding found six patients had a deletion detected by FISH; of these, only two had a microscopically visible chromosome deletion. Our study of 11 sets of parents of children with the deletion found two clinically affected mothers with the deletion, including one with three of three children clinically affected. A few patients who did not fit the classical VCF description had a 22q11.2 deletion detected by FISH. These included one patient with both cleft lip and palate, and another with developmental delay and typical facial features but no cardiac or palate abnormalities. Both patients with the DiGeorge anomaly as part of VCF had the deletion. On the other hand, a number of patients diagnosed clinically with classical VCF did not have a detectable deletion. This raises the question whether they represent a subset of patients with a defect of 22q11.2 not detected by the N25 probe, or whether they represent a phenocopy of VCF.

Ravnan, J.B.; Golabi, M.; Lebo, R.V. [Univ. of California, San Francisco, CA (United States)

1994-09-01

225

Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome  

Microsoft Academic Search

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14years with 22q11.2DS

Elliott A. Beaton; Yufeng Qin; Vy Nguyen; Joel Johnson; Joseph D. Pinter; Tony J. Simon

2010-01-01

226

Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML)  

Microsoft Academic Search

The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodys-plastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of

J. Stephenson; B. Czepulkowski; W. Hirst; G. J. Mufti

1996-01-01

227

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

Microsoft Academic Search

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).

Ramesh C. Juyal; P. I. Patel; F. Greenberg; James R. Lupski; Barbara J. Trask; Ger van den Engh; Elizabeth A. Lindsay; Heather Christy; Ken-Shiung Chen; Antonio Baldini; Lisa G. Shaffer

1995-01-01

228

Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene  

SciTech Connect

We report on the clinical and molecular characterization of 3 sibs with X-linked ichthyosis and variable expression of Kallmann syndrome. One of the affected brothers had mild hyposmia and showed normal pubertal progression. However, we demonstrated the same partial deletion of the X-linked Kallmann gene, sparing the first exon in the mildly affected patient as well as in one of his severely affected brothers. 13 refs., 1 fig., 1 tab.

Parenti, G.; Rizzolo, M.G.; Ghezzi, M. [Federico II University, Naples (Italy)] [and others

1995-07-03

229

Excess of deletions of maternal origin in the DiGeorge\\/Velo-cardio-facial syndromes. A study of 22 new patients and review of the literature  

Microsoft Academic Search

We have determined the parental origin of the deleted chromosome 22 in 29 cases of DiGeorge syndrome (DGS) using a CA-repeat mapping within the commonly deleted region, and in one other case by using a chromosome 22 short arm heteromorphism. The CA-repeat was informative in 21 out of 29 families studied and the deleted chromosome was of maternal origin in

Suzanne Demczuk; Annie Lévy; Muriel Aubry; Marie-Françoise Croquette; Nicole Philip; Marguerite Prieur; Ursula Sauer; Patrice Bouvagnet; Guy A. Rouleau; Gilles Thomas; Alain Aurias

1995-01-01

230

Contiguous gene deletion of TBX5 and TBX3 leads to a varible phenotype with combined features of Holt-Oram and ulnar-mammary syndromes.  

PubMed

We report on a combination of congenital malformations in a mother and her fetus harboring a heterozygous deletion encompassing the TBX5 and TBX3 genes, which are disease-causing in Holt-Oram and ulnar-mammary syndromes, respectively. This contiguous gene syndrome is reminiscent of Okihiro syndrome and emphasizes the importance of array-CGH as a diagnostic tool in atypical syndromic presentations with intrafamilial variability. PMID:23713051

Alby, Caroline; Bessieres, Bettina; Bieth, Eric; Attie-Bitach, Tania; Fermont, Laurent; Citony, Isabelle; Razavi, Ferechté; Vekemans, Michel; Escande, Fabienne; Manouvrier, Sylvie; Malan, Valérie; Amiel, Jeanne

2013-07-01

231

Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.  

PubMed

Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed. PMID:24035971

Passariello, Annalisa; De Brasi, Daniele; Defferrari, Raffaella; Genesio, Rita; Tufano, Maria; Mazzocco, Katia; Capasso, Maria; Migliorati, Roberta; Martinsson, Tommy; Siani, Paolo; Nitsch, Lucio; Tonini, Gian Paolo

2013-11-01

232

Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome  

Microsoft Academic Search

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly\\/mental retardation syndrome associated with del(17)(p11.2p11.2). The phenotype is variable even in patients with deletions of the same size. RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spec- trum of the phenotype remains unclear. Df(11)17\\/1 mice contain a heterozygous deletion

Jiong Yan; Victoria W. Keener; Weimin Bi; Katherina Walz; Allan Bradley; Monica J. Justice; James R. Lupski

2004-01-01

233

Testicular Expressed Genes Are Missing in Familial X-Linked Kallmann Syndrome due to Two Large Different Deletions in Daughter’s X Chromosomes  

Microsoft Academic Search

Background: X-linked Kallmann syndrome (KS) is caused mainly by point mutations, in the KAL1 gene. Large deletions >1 Mb are rare events in the human population and commonly result in contiguous gene syndromes. Methods: A search for the mutation causing KS carried out on two pairs of first-degree cousins of 2 sisters. Results: Two different apparently independent deletions were found.

Eli Hershkovitz; Neta Loewenthal; Asaf Peretz; Ruti Parvari

2008-01-01

234

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

235

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

236

Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome.  

PubMed

22q11.2 deletion syndrome (22q11DS) results from a hemizygous microdeletion on chromosome 22 and is characterized by extensive phenotypic variability. Penetrance of signs, including congenital heart, craniofacial, and neurobehavioral abnormalities, varies widely and is not well correlated with genotype. The three-dimensional structure of the genome may help explain some of this variability. The physical interaction profile of a given gene locus with other genetic elements, such as enhancers and co-regulated genes, contributes to its regulation. Thus, it is possible that regulatory interactions with elements outside the deletion region are disrupted in the disease state and modulate the resulting spectrum of symptoms. COMT, a gene within the commonly deleted ~3 Mb region has been implicated as a contributor to the neurological features frequently found in 22q11DS patients. We used this locus as bait in a 4C-seq experiment to investigate genome-wide interaction profiles in B lymphocyte and fibroblast cell lines derived from both 22q11DS and unaffected individuals. All normal B lymphocyte lines displayed local, conserved chromatin looping interactions with regions that are lost in atypical and distal deletions, which may mediate similarities between typical, atypical, and distal 22q11 deletion phenotypes. There are also distinct clusterings of cis interactions based on disease state. We identified regions of differential trans interactions present in normal, and lost in deletion-carrying, B lymphocyte cell lines. This data suggests that hemizygous chromosomal deletions such as 22q11DS can have widespread effects on chromatin organization, and may contribute to the inherent phenotypic variability. PMID:24448439

Zeitz, Michael J; Lerner, Paula P; Ay, Ferhat; Van Nostrand, Eric; Heidmann, Julia D; Noble, William S; Hoffman, Andrew R

2013-01-01

237

CATCH 22: deletion of locus 22q11 in velocardiofacial syndrome, DiGeorge anomaly, and nonsyndromic conotruncal defects.  

PubMed

DiGeorge anomaly (DGA) and velocardiofacial syndrome (VCFS) are frequently associated with monosomy of chromosomal subband 22q11. It is not clear whether individuals who present with only some of the features (e.g., isolated hypoparathyroidism or conotruncal defects) of these conditions also have the same deletion. In a prospective study of 30 children from 1994 to 1996, we used both high-resolution banding and fluorescence in situ hybridization (FISH) to assess the deletion status of children with a wide range of DGA-like or VCFS-like clinical features. Microdeletion of the chromosomal subband 22q11.22 was detected in 17 children by high-resolution banding and in two additional children with conotruncal defect (CTD) who had submicroscopic deletions proved by FISH analyses. Of the patients with microscopical deletion (n = 17), only six had classical DGA (n = 4) or VCFS (n = 2) phenotypes. The other 11 had various forms of congenital heart defects as the only presenting signs of deletion. One patient with DGA stigmata had another chromosomal aberration of monosomy 10p13. Only 10 patients were found to have neither cytogenetic nor molecular abnormalities. Therefore, it appeared that the majority, if not all, of the DGA and VCFS patients with the 22q11 deletion were identifiable using FISH with the single N25 (D22S75) probe. It would also be advisable that children with isolated CTD should be carefully examined to detect the other morphologic abnormalities of DGA and VCFS, or CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia/aplasia, cleft palate, hypocalcemia, and 22q11 deletion). Once these abnormalities are found, a molecular cytogenetic analysis for the so-called 22q11 region is indicated. Because of other associated chromosomal findings, routine or high-resolution cytogenetic analysis should be performed on patients with suspected CATCH 22. PMID:9216164

Hou, J W; Wang, J K; Tsai, W Y; Chou, C C; Wang, T R

1997-06-01

238

The 22q11.2 deletion syndrome as a window into complex neuropsychiatric disorders over the lifespan.  

PubMed

Evidence is rapidly accumulating that rare, recurrent copy number variants represent large effect risk factors for neuropsychiatric disorders. 22q11.2 deletion syndrome (22q11DS) (velocardiofacial syndrome or DiGeorge syndrome) is the most common known contiguous gene deletion syndrome and is associated with diverse neuropsychiatric disorders across the life span. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum, attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson's disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated autism spectrum disorder and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here, we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder's heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system. PMID:23992925

Jonas, Rachel K; Montojo, Caroline A; Bearden, Carrie E

2014-03-01

239

Comparative Mapping of the Region of Human Chromosome 7 Deleted in Williams Syndrome  

PubMed Central

Williams syndrome (WS) is a complex developmental disorder resulting from the deletion of a large (?1.5–2 Mb) segment of human chromosome 7q11.23. Physical mapping studies have revealed that this deleted region, which contains a number of known genes, is flanked by several large, nearly identical blocks of DNA. The presence of such highly related DNA segments in close physical proximity to one another has hampered efforts to elucidate the precise long-range organization of this segment of chromosome 7. To gain insight about the structure and evolutionary origins of this important and complex genomic region, we have constructed a fully contiguous bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) contig map encompassing the corresponding region on mouse chromosome 5. In contrast to the difficulties encountered in constructing a clone-based physical map of the human WS region, the BAC/PAC-based map of the mouse WS region was straightforward to construct, with no evidence of large duplicated segments, such as those encountered in the human WS region. To confirm this difference, representative human and mouse BACs were used as probes for performing fluorescence in situ hybridization (FISH) to metaphase and interphase chromosomes. Human BACs derived from the nonunique portion of the WS region hybridized to multiple, closely spaced regions on human chromosome 7q11.23. In contrast, corresponding mouse BACs hybridized to a single site on mouse chromosome 5. Furthermore, FISH analysis revealed the presence of duplicated segments within the WS region of various nonhuman primates (chimpanzee, gorilla, orangutan, and gibbon). Hybridization was also noted at the genomic locations corresponding to human chromosome 7p22 and 7q22 in human, chimpanzee, and gorilla, but not in the other animal species examined. Together, these results indicate that the WS region is associated with large, duplicated blocks of DNA on human chromosome 7q11.23 as well as the corresponding genomic regions of other nonhuman primates. However, such duplications are not present in the mouse.

DeSilva, Udaya; Massa, Hillary; Trask, Barbara J.; Green, Eric D.

1999-01-01

240

A contiguous gene deletion syndrome at 7q21-q22 and implications for a relationship between isolated ectrodactyly and syndromic ectrodactyly.  

PubMed

Ectrodactyly is a genetically heterogeneous human limb developmental malformation with an autosomal locus at 7q21 designated SHFD1. We report a patient with ectrodactyly and a small interstitial deletion of 7q21, detected by high resolution karyotype, which provides additional evidence for the existence of an ectrodactyly gene in this region and further restricts the size of the critical region containing SHFD1. A review of previously published patients with ectrodactyly and similar deletions suggests a contiguous gene deletion syndrome at 7q21-q22 which consists of ectrodactyly, growth retardation, developmental delay, hypertelorism, ear malformation, components of the Robin sequence, and GU abnormalities. Moreover, the clinical, genetic, and cytogenetic similarities of a number of multiple congenital anomaly syndromes which include ectrodactyly as just one component lead us to propose that a common genetic basis may underlie many of these syndromes. Thus, evaluation for related physical anomalies and high resolution cytogenetic studies are indicated in patients with ectrodactyly. PMID:7894731

Nunes, M E; Pagon, R A; Disteche, C J; Evans, J P

1994-10-01

241

Twelve new patients with 13q deletion syndrome: Genotype–phenotype analyses in progress  

Microsoft Academic Search

13q deletion is characterized by a wide phenotypic spectrum resulting from a partial deletion of the long arm of chromosome 13. The main clinical features are mental retardation, growth retardation, craniofacial dysmorphy and various congenital defects. Only one recent Italian study was aimed at determining genotype–phenotype correlations among 13q deletions from a group of mainly live born children, using array-CGH

Chloé Quélin; Claude Bendavid; Christèle Dubourg; Céline de la Rochebrochard; Josette Lucas; Catherine Henry; Sylvie Jaillard; Philippe Loget; Laurence Loeuillet; Didier Lacombe; Jean-Marie Rival; Véronique David; Sylvie Odent; Laurent Pasquier

2009-01-01

242

A novel and de novo deletion in the OCRL1 gene associated with a severe form of Lowe syndrome.  

PubMed

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate (PIP2P) 5-phosphatase, is responsible for the phenotypic characteristics of the disease. We report a 22-year-old male with a severe form of OCRL syndrome, diagnosed on the basis of congenital cataracts, severe psychomotor and cognitive deficits, and renal tubular dysfunction without Fanconi syndrome. The patient presented low molecular weight proteinuria, nephrocalcinosis, nephrolithiasis, rickets, and growth retardation and developed progressive renal failure. Genetic analysis showed a novel and de novo deletion of exons 10-13 in the OCRL1 gene. PMID:22821049

Peces, Ramón; Peces, Carlos; de Sousa, Erika; Vega, Cristina; Selgas, Rafael; Nevado, Julián

2013-12-01

243

Antibody deficiency in adults with 22q11.2 deletion syndrome.  

PubMed

There are limited data on immunological disorders, infection profile, and autoimmunity among adults with the 22q11.2 deletion syndrome (22q11.2DS) in the literature. To expand this knowledge base, we evaluated immunoglobulin levels, lymphocyte subsets, and T-cell function in 26 adults, consecutively referred to our 22q11.2DS multidisciplinary team. Their medical records were also reviewed with respect to frequency and severity of infections and autoimmune disorders. Six patients had low immunoglobulin levels; among these patients, one had a combined IgA and IgG1 deficiency, one had an isolated IgG3 deficiency, and four had a profound antibody deficiency comparable to common variable immunodeficiency (CVID). Three of the patients with profound antibody deficiency showed signs of reduced T-cell function measured as a low response to mitogen and/or antigen stimulation. The four patients with profound antibody deficiency suffered from more severe infections than the rest of the patient group. Three of them also had a history of both immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AHA). Our results suggest that a subgroup of individuals with 22q11.2DS can develop a severe antibody deficiency associated with lower respiratory tract infections and autoimmune conditions. Early diagnosis of hypogammaglobulinemia among these individuals is important in order to provide optimal treatment. We therefore recommend an immunological evaluation and follow-up among adults with 22q11.2DS who have a history of autoimmune conditions or recurrent infections. PMID:22786729

Björk, Aron H; Óskarsdóttir, Sólveig; Andersson, Bengt A; Friman, Vanda

2012-08-01

244

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.

Kon, Moshe; Mink van der Molen, Aebele B

2014-01-01

245

A search for chromosome 22q11.2 deletions in a series of 176 consecutively catheterized patients with congenital heart disease: no evidence for deletions in non-syndromic patients  

Microsoft Academic Search

Microdeletions in chromosome 22q11.2 are associated with DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and\\u000a several other syndromes, collectively referred to as DG\\/VCF. Non-dysmorphic patients with cardiac defects have also been attributed\\u000a to deletions in this chromosomal region. In this study 157 consecutively catheterized patients with isolated, non-syndromic\\u000a cardiac defects, and 25 patients with cardiac defects and additional stigmata (10 of

S. Borgmann; I. Luhmer; M. Arslan-Kirchner; H.-C. Kallfelz; J. Schmidtke

1999-01-01

246

Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.  

PubMed

Heterozygous mutations in MSX2 are responsible for an autosomal dominant form of parietal foramina (PFM). PFM are oval defects of the parietal bones that are also a characteristic feature of a contiguous gene-deletion syndrome caused by a proximal deletion in the short arm of chromosome 11 (Potocki-Shaffer syndrome). We have identified a human bacterial artificial chromosome (BAC) clone mapping to chromosome 11, containing a region homologous to the human homeobox gene MSX2. Further sequence analysis demonstrated that the human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is contained within this 11p clone. We used FISH to test for the presence-or for the heterozygous deletion-of this clone in two patients with the 11p11.2-deletion syndrome and showed that this clone is deleted in these patients. ALX4 and Alx4 were shown to be expressed in bone and to be absent from all other tissues tested. The involvement of Alx4 in murine skull development, its bone-specific expression pattern, the fact that Alx4 is a dosage-sensitive gene in mice, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, support the contention that ALX4 is a candidate gene for the PFM in the 11p11.2-deletion syndrome. PMID:11017806

Wu, Y Q; Badano, J L; McCaskill, C; Vogel, H; Potocki, L; Shaffer, L G

2000-11-01

247

Haploinsufficiency of ALX4 as a Potential Cause of Parietal Foramina in the 11p11.2 Contiguous Gene-Deletion Syndrome  

PubMed Central

Heterozygous mutations in MSX2 are responsible for an autosomal dominant form of parietal foramina (PFM). PFM are oval defects of the parietal bones that are also a characteristic feature of a contiguous gene–deletion syndrome caused by a proximal deletion in the short arm of chromosome 11 (Potocki-Shaffer syndrome). We have identified a human bacterial artificial chromosome (BAC) clone mapping to chromosome 11, containing a region homologous to the human homeobox gene MSX2. Further sequence analysis demonstrated that the human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is contained within this 11p clone. We used FISH to test for the presence—or for the heterozygous deletion—of this clone in two patients with the 11p11.2-deletion syndrome and showed that this clone is deleted in these patients. ALX4 and Alx4 were shown to be expressed in bone and to be absent from all other tissues tested. The involvement of Alx4 in murine skull development, its bone-specific expression pattern, the fact that Alx4 is a dosage-sensitive gene in mice, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, support the contention that ALX4 is a candidate gene for the PFM in the 11p11.2-deletion syndrome.

Wu, Yuan-Qing; Badano, Jose L.; McCaskill, Christopher; Vogel, Hannes; Potocki, Lorraine; Shaffer, Lisa G.

2000-01-01

248

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

249

Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome.  

PubMed

Rubinstein-Taybi syndrome is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation, psychomotor developmental delay, skeletal anomalies, peculiar facial morphology, and tumorigenesis. Mutations in the gene encoding the cAMP response element-binding protein (CREB, also known as CREBBP or CBP) on chromosome 16p13.3 have been identified. In addition, some patients with low intelligence quotients and autistic features bear large deletions. Based on these observations, we used multiplex ligation-dependent probe amplification to search for large deletions affecting the CREBBP gene in a Rubinstein-Taybi syndrome patient. We identified a novel heterozygote deletion removing five exons (exons 17-21), encoding the histone acetyltransferase domain. We propose the use of multiplex ligation-dependent probe amplification as a fast, accurate and cheap test for detecting large deletions in the CREBBP gene in the sub-group of Rubinstein-Taybi syndrome patients with low intelligence quotients and autistic features. PMID:23315884

Calì, F; Failla, P; Chiavetta, V; Ragalmuto, A; Ruggeri, G; Schinocca, P; Schepis, C; Romano, V; Romano, C

2013-01-01

250

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

PubMed Central

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-Down syndrome (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 two 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.

Loudin, Michael G.; Wang, Jinhua; Leung, Hon-Chiu Eastwood; Gurusiddappa, Sivashankarappa; Meyer, Julia; Condos, Gregory; Morrison, Debra; Tsimelzon, Anna; Devidas, Meenakshi; Heerema, Nyla A.; Carroll, Andrew J.; Plon, Sharon E.; Hunger, Stephen P.; Basso, Giuseppe; Pession, Andrea; Bhojwani, Deepa; Carroll, William L.; Rabin, Karen R.

2014-01-01

251

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.

2014-01-01

252

Is Dandy-Walker malformation associated with "distal 13q deletion syndrome"? Findings in a fetus supporting previous observations.  

PubMed

We report on a fetus with a large deletion of the distal part of the long arm of chromosome 13, (del(13)(q14 --> qter)) congenital anomalies of the urinary system, lungs and extremities, and Dandy-Walker malformation (DWM). Although DWM has been associated with many chromosomal abnormalities and genetic syndromes, its relation to the distal 13q has been demonstrated recently. In 2002, McCormack et al., described two patients with deletions of the long arm of chromosome 13 who had multiple congenital abnormalities along with holoprosencephaly (HPE) and DWM. The phenotypic features and autopsy findings of a fetus with "distal 13q deletion syndrome" at 22 weeks gestation are discussed and comparison with the previous two cases is made. The findings support the previous hypothesis suggesting that haploinsufficiency at a locus within 13q22-33 due to microdeletions may be responsible for isolated DWM in some of the patients. Detailed examination of 13q (13q22-33) by means of conventional and molecular cytogenetic methods is necessary in cases with DWM. PMID:15948192

Alanay, Yasemin; Akta?, Dilek; Utine, Eda; Talim, Beril; Ondero?lu, Lütfü; Ca?lar, Melda; Tunçbilek, Ergül

2005-07-30

253

A case of 9.7 Mb terminal Xp deletion including OA1 locus associated with contiguous gene syndrome.  

PubMed

Terminal or interstitial deletions of Xp (Xp22.2?Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea. PMID:23091330

Cho, Eun-Hae; Kim, Sook-Young; Kim, Jin-Kyung

2012-10-01

254

Seizures as the first manifestation of chromosome 22q11.2 deletion syndrome in a 40-year old man: a case report  

Microsoft Academic Search

BACKGROUND: The microdeletion of chromosome 22q11.2 is the most common human deletion syndrome. It typically presents early in life and is rarely considered in adult patients. As part of the manifestations of this condition, patients can have parathyroid glandular involvement ranging from hypocalcemic hypoparathyroidism to normocalcemia with normal parathryroid hormone levels. The first manifestation of the syndrome might be seizures

Adriano R Tonelli; Kalyan Kosuri; Sainan Wei; Davoren Chick

2007-01-01

255

Identification of the first intragenic deletion of the PITX2 gene causing an Axenfeld-Rieger Syndrome: case report  

PubMed Central

Background Axenfeld-Rieger syndrome (ARS) is characterized by bilateral congenital abnormalities of the anterior segment of the eye associated with abnormalities of the teeth, midface, and umbilicus. Most cases of ARS are caused by mutations in the genes encoding PITX2 or FOXC1. Here we describe a family affected by a severe form of ARS. Case presentation Two members of this family (father and daughter) presented with typical ARS and developed severe glaucoma. The ocular phenotype was much more severe in the daughter than in the father. Magnetic resonance imaging (MRI) detected an aggressive form of meningioma in the father. There was no mutation in the PITX2 gene, determined by exon screening. We identified an intragenic deletion by quantitative genomic PCR analysis and characterized this deletion in detail. Conclusion Our findings implicate the first intragenic deletion of the PITX2 gene in the pathogenesis of a severe form of ARS in an affected family. This study stresses the importance of a systematic search for intragenic deletions in families affected by ARS and in sporadic cases for which no mutations in the exons or introns of PITX2 have been found. The molecular genetics of some ARS pedigrees should be re-examined with enzymes that can amplify medium and large genomic fragments.

de la Houssaye, Guillaume; Bieche, Ivan; Roche, Olivier; Vieira, Veronique; Laurendeau, Ingrid; Arbogast, Laurence; Zeghidi, Hatem; Rapp, Philippe; Halimi, Philippe; Vidaud, Michel; Dufier, Jean-Louis; Menasche, Maurice; Abitbol, Marc

2006-01-01

256

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency  

PubMed Central

Background 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome. Methods A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. Results Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. Conclusions This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

2013-01-01

257

Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for our times.  

PubMed

The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. Conclusion: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources. PMID:24384789

Habel, Alex; Herriot, Richard; Kumararatne, Dinakantha; Allgrove, Jeremy; Baker, Kate; Baxendale, Helen; Bu'Lock, Frances; Firth, Helen; Gennery, Andrew; Holland, Anthony; Illingworth, Claire; Mercer, Nigel; Pannebakker, Merel; Parry, Andrew; Roberts, Anne; Tsai-Goodman, Beverly

2014-06-01

258

Distal 6p deletion syndrome: a report of a case with anterior chamber eye anomaly and review of published reports.  

PubMed Central

We describe a 32 year old male with a distal 6p24.3-->pter deletion. He has specific developmental anomalies of the anterior chamber of the eye and a cleft uvula which is consistent with the recent localisation of genes for iris development and orofacial clefting to distal 6p. In addition he has progressive sensorineural deafness and this may localise a gene for deafness to this region. We conclude that a refined distal 6p deletion syndrome exists and includes a characteristic facial appearance with hypertelorism, downward slanting palpebral fissures, tented mouth, smooth philtrum, palatal malformation, ear anomalies, anterior chamber eye defects, progressive sensorineural deafness, cardiac defects, abdominal herniae, small external genitalia, and motor and speech delay. Images

Law, C J; Fisher, A M; Temple, I K

1998-01-01

259

Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: association with an 18p11.3 deletion.  

PubMed

We report a patient with a unique combination of features, including microcephaly; mental retardation; poorly developed frontal lobes; hypoplastic pituitary gland; hypothyroidism; alopecia universalis; single maxillary central incisor; taurodontism; median palatal ridge; longitudinally grooved nails; and scoliosis. His unbalanced karyotype was found to be 45,XY,der(15;18)(q10;q10). The constellation of anomalies appears to represent a contiguous gene syndrome caused, at least in part, by deletion of TGIF and the gene responsible for hereditary hypotrichosis simplex. The phenotype of our patient differs other reported patients with del(18p). Possible explanations include (1) the effects of a different deleted region, (2) a positional effect caused by a gene close by, or (3) by interruption of a different gene resulting from chromosomal translocation. PMID:17001671

Kantaputra, Piranit N; Limwongse, Chanin; Tochareontanaphol, Chintana; Mutirangura, Apiwat; Mevatee, Umnat; Praphanphoj, Verayuth

2006-12-01

260

Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome.  

PubMed

22q11.2 deletion syndrome (22q11.2DS) is caused by a commonly occurring microdeletion on chromosome 22. Clinical findings include cardiac malformations, thymic and parathyroid hypoplasia, craniofacial dysmorphisms, and dental defects. These phenotypes are due mainly to abnormal development of the pharyngeal apparatus. Targeted deletion studies in mice and analysis of naturally occurring mutations in humans have implicated Tbx1 as a candidate gene for 22q11.2DS. Tbx1 belongs to an evolutionarily conserved T-box family of transcription factors, whose expression is precisely regulated during embryogenesis, and it appears to regulate the proliferation and differentiation of various progenitor cells during organogenesis. In this review, we discuss the mechanisms of Tbx1 during development of the heart, thymus and parathyroid glands, as well as during formation of the palate, teeth, and other craniofacial features. PMID:23996541

Gao, Shan; Li, Xiao; Amendt, Brad A

2013-12-01

261

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.

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

2014-01-01

262

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

263

Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2  

SciTech Connect

The so-called {open_quotes}conotruncal anomaly face syndrome{close_quotes} (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet ring ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients, 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other know malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. 20 refs., 3 figs., 2 tabs.

Matsuoka, Rumiko; Takao, Atsuyoshi; Kimura, Misa; Kondo, Chisato; Ando, Masahiko; Momma, Kazuo; Imamura, Shin-ichiro [Heart Institute, Tokyo (Japan); Joh-o, Kunitaka [Welfare Pension Hospital, Kyushu (Japan); Ikeda, Kazuo [Sapporo Medical Univ. (Japan); Nishibatake, Makoto [Kagoshima Seikyo Hospital (Japan)

1994-11-15

264

Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2.  

PubMed

The so-called "conotruncal anomaly face syndrome" (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other known malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. PMID:7856665

Matsuoka, R; Takao, A; Kimura, M; Imamura, S; Kondo, C; Joh-o, K; Ikeda, K; Nishibatake, M; Ando, M; Momma, K

1994-11-15

265

JAG1 mutation in a patient with deletion 22q11.2 syndrome and tetralogy of Fallot.  

PubMed

Deletion 22q11.2 (del22q11.2) syndrome, also known as DiGeorge/Velo-cardio-facial syndrome (DG/VCFS), and Alagille syndrome are genetic disorders characteristically associated with congenital heart defects (CHDs). We report on a patient with tetralogy of Fallot (TOF) and clinical features of DG/VCFS, hemizygous for del22q11.2 and heterozygous for the 2810G > A (p.Arg937Gln) mutation in the JAG1 gene associated with Alagille syndrome. The clinical features of del22q11.2 syndrome are present in the patient, including facial anomalies, typical TOF, speech delay with hypernasal voice, and learning difficulties. TOF and mild hepatic involvement, consisting of slightly elevated aminotransferase conjugated bilirubin levels, were the only features of Alagille syndrome in our patient. The anatomic type of TOF displayed no distinctive recognizable pattern for either DG/VCFS or Alagille syndrome. It is likely that hemizygosity of the TBX1 gene was causally related to TOF in this patient, although a synergistic pathogenic role of the JAG1 gene mutation in causing the heart defect cannot be excluded. JAG1 mutations have been previously detected in patients with nonsyndromic TOF and recent molecular evidence supports the cumulative effect of multiple genetic defects in the etiology of human malformations. We hypothesize that a similar mechanism could be present in this patient with del22q11.2 syndrome associated with a JAG1 missense mutation acting as possible modifier factor for TOF. PMID:23956173

Digilio, Maria Cristina; Luca, Alessandro De; Lepri, Francesca; Guida, Valentina; Ferese, Rosangela; Dentici, Maria Lisa; Angioni, Adriano; Marino, Bruno; Dallapiccola, Bruno

2013-12-01

266

Human homologue sequences to the Drosophila dishevelled segment-polarity gene are deleted in the DiGeorge syndrome  

SciTech Connect

DiGeorge syndrome (DGS) is a developmental defect of some of the neural crest derivatives. Most DGS patients show haploinsufficiency due to interstitial deletions of the proximal long arm of chromosome 22. Deletions of 22q11 have also been reported in patients with the velo-cardio-facial syndrome and familial conotruncal heart defects. It has been suggested that the wide phenotype spectrum associated with 22q11 monosomy is a consequence of contiguous-gene deletions. We report the isolation of human cDNAs homologous to the Drosophila dishevelled (dsh) segment-polarity gene. Sequences homologous to the 3{prime} UTR of these transcripts (DVL-22) were positioned within the DGS critical region and were found to be deleted in DGS patients. Human DVL mRNAs are expressed in several fetal and adult tissues, including the thymus and, at high levels, the heart. Two transcripts, 3.2 and 5 kb, were detected, in Northern blot analysis, with different expression patterns in the surveyed tissues when different cDNAs were used. The isolated cDNAs exhibit high amino acid homology with the mouse and Xenopus Dvl-1 gene, the only other vertebrate dsh homologues so far isolated. The pivotal role of dsh in fly development suggests an analogous key function in vertebrate embryogenesis of its homologue genes. Since DGS may be due to perturbation of differentiation mechanisms at decisive embryological stages, a Dsh-like gene in the small-region overlap (SRO) might be a candidate for the pathogenesis of this disorder. 52 refs., 3 figs.

Pizzuti, A.; Ratti, A.; Penso, D.; Silani, V.; Scarlato, G. [Universita di Milano, Milan (Italy)] [and others

1996-04-01

267

Human homologue sequences to the Drosophila dishevelled segment-polarity gene are deleted in the DiGeorge syndrome.  

PubMed Central

DiGeorge syndrome (DGS) is a developmental defect of some of the neural crest derivatives. Most DGS patients show haploinsufficiency due to interstitial deletions of the proximal long arm of chromosome 22. Deletions of 22q11 have also been reported with patients with the velocardio-facial syndrome and familial conotruncal heart defects. It has been suggested that the wide phenotype spectrum associated with 22q11 monosomy is a consequence of contiguous-gene deletions. We report the isolation of human cDNAs homologous to the Drosophila dishevelled (dsh) segment-polarity gene. Sequences homologous to the 3' UTR of these transcripts (DVL-22) were positioned within the DGS critical region and were found to be deleted in DGS patients. Human DVL mRNAs are expressed in several fetal and adult tissues, including the thymus and, at high levels, the heart. Two transcripts, 3.2 and 5kb, were detected, in northern blot analysis, with different expression patterns in the surveyed tissues when different cDNAs were used. The isolated cDNAs exhibit high amino acid homology with the mouse and Xenopus Dvl-1 gene, the only other vertebrate dsh homologues so far isolated. The pivotal role of dsh in fly development suggests an analogous key function in vertebrate embryogenesis of its homologue genes. Since DGS may be due to perturbation of differentiation mechanisms at decisive embryological stages, a Dsh-like gene in the small-region overlap (SRO) might be a candidate for the pathogenesis of this disorder. Images Figure 1 Figure 2 Figure 3

Pizzuti, A.; Novelli, G.; Mari, A.; Ratti, A.; Colosimo, A.; Amati, F.; Penso, D.; Sangiuolo, F.; Calabrese, G.; Palka, G.; Silani, V.; Gennarelli, M.; Mingarelli, R.; Scarlato, G.; Scambler, P.; Dallapiccola, B.

1996-01-01

268

Evaluation of Potential Modifiers of the Cardiac Phenotype in the 22q11.2 Deletion Syndrome  

PubMed Central

BACKGROUND The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher’s exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region.

Goldmuntz, Elizabeth; Driscoll, Deborah A.; Emanuel, Beverly S.; McDonald-McGinn, Donna; Mei, Minghua; Zackai, Elaine; Mitchell, Laura E.

2010-01-01

269

Myelodysplastic syndrome in childhood: report of two cases with deletion of chromosome 4 and the Philadelphia chromosome.  

PubMed

We report two pediatric patients with unclassified myelodysplastic syndrome (MDS) by the French-American-British (FAB) group. Both cases had clinical and hematological peculiarities, which had not been described yet. The cytogenetic alterations were 4q deletion and the Philadelphia (Ph) chromosome which appeared at different moments of the disease. One patient showed the Ph chromosome at disease transformation and the other at diagnosis. The different breakpoints at 4q and the presence of Ph could be a marker of this form of MDS. The association of clinical and hematological findings suggests the possibility of a new group of pediatric MDS. PMID:12007500

Dalla Torre, Cristiane Arruda; de Martino Lee, Maria Lucia; Yoshimoto, Maisa; Lopes, Luiz Fernando; Melo, Ligia Niero; Caminada de Toledo, Silvia Regina; Duffles Andrade, Joyce Anderson

2002-06-01

270

Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q 11-12.  

PubMed

Wolcott-Rallison syndrome is a rare autosomal recessive condition first described in 1972. It is characterised by diabetes mellitus which arises in early infancy and multiple epiphyseal dysplasia. We describe an affected girl who had recurrent episodes of hepatic failure for which no obvious cause was found. Post-mortem examination revealed abnormal pancreatic histology and congenital abnormalities of the central nervous and cardio-respiratory systems which have not been previously described in this condition. She also demonstrated a deletion at 15q 11-12 in 65% of her cells. PMID:8737981

Stewart, F J; Carson, D J; Thomas, P S; Humphreys, M; Thornton, C; Nevin, N C

1996-03-01

271

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

272

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

273

Molecular analysis of chromosome 11 deletions in aniridia-Wilms tumor syndrome.  

PubMed Central

We describe five individuals who have constitutional deletions of the short arm of one chromosome 11, including all or part of the band p13. All of these individuals suffer from aniridia; two have had a Wilms tumor removed. We have established lymphoblastoid cell lines from these and in three cases constructed somatic cell hybrids containing the deleted chromosome 11. Analysis of DNA from the cell lines and hybrids with a cloned cDNA probe has shown that the catalase gene is deleted in four of five patients. The catalase locus must be proximal to the Wilms and aniridia-related loci. We have not detected a deletion of the beta-globin or calcitonin genes in any of these individuals; we conclude these genes are likely to be outside the region 11p12-11p15.4. In addition, we have used monoclonal antibodies in fluorescence-activated cell sorting analysis to measure expression in the hybrids of two cell surface markers encoded by genes that map to the short arm of chromosome 11. The genes for both of these are deleted in two individuals but are present in the individual with the smallest deletion. Images

van Heyningen, V; Boyd, P A; Seawright, A; Fletcher, J M; Fantes, J A; Buckton, K E; Spowart, G; Porteous, D J; Hill, R E; Newton, M S

1985-01-01

274

Deletion 4q21/4q22 syndrome: Two patients with de novo 4q21.3q23 and 4q13.2q23 deletions  

SciTech Connect

We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosome 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/ 4q22 region reported previously detected a characteristic phenotype in 8 patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region. 39 refs., 6 figs., 1 tab.

Nowaczyk, M.J.M.; Seigel-Bartelt, J.; Clarke, J.T.R. [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)] [and others] [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada); and others

1997-04-14

275

Single Nucleotide Deletion Mutation of KCNH2 Gene is Responsible for LQT Syndrome in a 3-Generation Korean Family  

PubMed Central

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart.

Park, Jong Keun; Oh, Yong-Seog; Choi, Jee-hyun

2013-01-01

276

Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.  

PubMed

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart. PMID:24015048

Park, Jong Keun; Oh, Yong-Seog; Choi, Jee-hyun; Yoon, Sungjoo Kim

2013-09-01

277

A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome  

PubMed Central

The Prader–Willi syndrome (PWS) is caused by a 5–6?Mbp de novo deletion on the paternal chromosome 15, maternal uniparental disomy 15 or an imprinting defect. All three lesions lead to the lack of expression of imprinted genes that are active on the paternal chromosome only: MKRN3, MAGEL2, NDN, C15orf2, SNURF-SNRPN and more than 70 C/D box snoRNA genes (SNORDs). The contribution to PWS of any of these genes is unknown, because no single gene mutation has been described so far. We report on two patients with PWS who have an atypical deletion on the paternal chromosome that does not include MKRN3, MAGEL2 and NDN. In one of these patients, NDN has a normal DNA methylation pattern and is expressed. In another patient, the paternal alleles of these genes are deleted as the result of an unbalanced translocation 45,X,der(X)t(X;15)(q28;q11.2). This patient is obese and mentally retarded, but does not have PWS. We conclude that a deficiency of MKRN3, MAGEL2 and NDN is not sufficient to cause PWS.

Kanber, Deniz; Giltay, Jacques; Wieczorek, Dagmar; Zogel, Corinna; Hochstenbach, Ron; Caliebe, Almuth; Kuechler, Alma; Horsthemke, Bernhard; Buiting, Karin

2009-01-01

278

A novel seven-base deletion of the CTSC gene identified in a Hungarian family with Papillon-Lefèvre syndrome.  

PubMed

Papillon-Lefévre syndrome (PLS; OMIM 245000) is a rare autosomal recessive condition characterized by symmetrical palmoplantar hyperkeratosis and periodontal inflammation, causing loss of both the deciduous and permanent teeth. PLS develops due to mutations in the cathepsin C gene, CTSC. Recently we have identified a Hungarian PLS family with two affected siblings. Direct sequencing of the coding regions of the CTSC gene revealed a novel seven-base deletion leading to frameshift and early stop codon in the fourth exon of the CTSC gene (c.681delCATACAT, p.T188fsX199). The affected family members carried the mutation in homozygous form, while the clinically unaffected family members carried the mutation in heterozygous form. The unrelated controls carried only the wild type sequence. In this paper we report a novel homozygous deletion of seven bases on the CTSC gene leading to the development of PLS. Since consanguineous marriage was unknown in the investigated family, the presence of the homozygous seven-base deletion of the CTSC gene may suggest that the parents are close relatives. PMID:23397598

Farkas, Katalin; Paschali, Ekaterine; Papp, Ferenc; Vályi, Péter; Széll, Márta; Kemény, Lajos; Nagy, Nikoletta; Csoma, Zsanett

2013-07-01

279

Converging levels of analysis on a genomic hotspot for psychosis: Insights from 22q11.2 Deletion Syndrome  

PubMed Central

Schizophrenia is a devastating neurodevelopmental disorder that, despite extensive research, still poses a considerable challenge to attempts to unravel its heterogeneity, and the complex biochemical mechanisms by which it arises. While the majority of cases are of unknown etiology, accumulating evidence suggests that rare genetic mutations, such as 22q11.2 Deletion Syndrome (22qDS), can play a significant role in predisposition to the illness. Up to 25% of individuals with 22qDS eventually develop schizophrenia; conversely, this deletion is estimated to account for 1–2% of schizophrenia cases overall. This locus of Chromosome 22q11.2 contains genes that encode for proteins and enzymes involved in regulating neurotransmission, neuronal development, myelination, micro RNA processing, and posttranslational protein modifications. As a consequence of the deletion, affected individuals exhibit cognitive dysfunction, structural and functional brain abnormalities, and neurodevelopmental anomalies that parallel many of the phenotypic characteristics of schizophrenia. As an illustration of the value of rare, highly penetrant genetic subtypes for elucidating pathological mechanisms of complex neuropsychiatric disorders, we provide here an overview of the cellular, network, and systems-level anomalies found in 22qDS, and review the intriguing evidence for this disorder’s association with schizophrenia. This article is part of a Special Issue entitled ‘Neurodevelopmental Disorders’.

Schreiner, Matthew J.; Lazaro, Maria T.; Jalbrzikowski, Maria; Bearden, Carrie E.

2012-01-01

280

Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease.  

PubMed

The severe acute respiratory syndrome coronavirus (SARS-CoV) caused substantial morbidity and mortality in 2002-2003. Deletion of the envelope (E) protein modestly diminished virus growth in tissue culture but abrogated virulence in animals. Here, we show that immunization with rSARS-CoV-DeltaE or SARS-CoV-Delta[E,6-9b] (deleted in accessory proteins (6, 7a, 7b, 8a, 8b, 9b) in addition to E) nearly completely protected BALB/c mice from fatal respiratory disease caused by mouse-adapted SARS-CoV and partly protected hACE2 Tg mice from lethal disease. hACE2 Tg mice, which express the human SARS-CoV receptor, are extremely susceptible to infection. We also show that rSARS-CoV-DeltaE and rSARS-CoV-Delta[E,6-9b] induced anti-virus T cell and antibody responses. Further, the E-deleted viruses were stable after 16 blind passages through tissue culture cells, with only a single mutation in the surface glycoprotein detected. The passaged virus remained avirulent in mice. These results suggest that rSARS-CoV-DeltaE is an efficacious vaccine candidate that might be useful if SARS recurred. PMID:20110095

Netland, Jason; DeDiego, Marta L; Zhao, Jincun; Fett, Craig; Alvarez, Enrique; Nieto-Torres, José L; Enjuanes, Luis; Perlman, Stanley

2010-03-30

281

Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and/or mental retardation  

PubMed Central

Background Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing. Results 296 patients with MR and a normal karyotype (500–550 bands) were screened for subtelomeric imbalances by using qPCR combined with SYBR green detection. In total, 17 patients (5.8%) with 20 subtelomeric imbalances were identified. Six of the aberrations (2%) were classified as causative for the symptoms, because they occurred either de novo in the patients (5 cases) or the aberration were be detected in the patient and an equally affected parent (1 case). The extent of the deletions ranged from 1.8 to approximately 10 Mb, duplications were 1.8 to approximately 5 Mb in size. In 6 patients, the copy number variations (CNVs) were rated as benign polymorphisms, and the clinical relevance of these CNVs remains unclear in 5 patients (1.7%). Therefore, the overall frequency of clinically relevant imbalances ranges between 2% and 3.7% in our cohort. Conclusion This study illustrates that the qPCR/SYBR green technique represents a rapid and versatile method for the detection of subtelomeric imbalances and the option to map the breakpoint. Thus, this technique is highly suitable for genotype/phenotype studies in patients with MR/developmental delay and/or congenital defects.

Auber, Bernd; Bruemmer, Verena; Zoll, Barbara; Burfeind, Peter; Boehm, Detlef; Liehr, Thomas; Brockmann, Knut; Wilichowski, Ekkehard; Argyriou, Loukas; Bartels, Iris

2009-01-01

282

Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader-Willi syndrome.  

PubMed

Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11-q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IC) deletion (PWS IC deletion). These mice die generally within 2-3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5-fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro-opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 7B). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription-PCR (RT-PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS. PMID:17036336

Bittel, Douglas C; Kibiryeva, Nataliya; McNulty, Steven G; Driscoll, Daniel J; Butler, Merlin G; White, Robert A

2007-03-01

283

Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation.  

PubMed

Contiguous gene syndromes are an interesting clinical phenomenon, resulting from interstitial or terminal deletions of several adjacent genes. The phenotype results in a combination of two or more monogenic disorders and relates clinical findings to corresponding genotypes. We present the case of a male patient with Kallmann syndrome (KS), X-linked ichthyosis (XLI) and X-linked mental retardation (MRX). He was referred at the age of 15.4 years for delayed puberty and obesity. He had a previous history of pyloric stenosis, bilateral orchidopexy and surgical correction of a pes equinovarus adductus. On physical examination, generalised ichthyosis and hypoplastic external genitalia were found. KS was evident with hypogonadotropic hypogonadism, hyposmia and a hypoplastic anlage of the olfactory tract in magnetic resonance imaging. Lipoprotein electrophoresis, and lack of steroid sulfatase and arylsulfatase-C activity in leucocytes confirmed XLI. DNA investigation established an interstitial deletion in Xp22.3 involving the Kallmann (KAL) gene, the steroid sulfatase (STS) gene and a putative mental retardation locus (MRX). The novel MRX locus maps to a 1-Mb region between DXS1060 and GS1. PMID:9727739

Weissörtel, R; Strom, T M; Dörr, H G; Rauch, A; Meitinger, T

1998-07-01

284

Novel 47.5-kb deletion in RAB27A results in severe Griscelli Syndrome type 2  

PubMed Central

Griscelli syndrome (GS), a rare autosomal recessive disorder characterized by partial albinism and immunological impairment and/or severe neurological impairment, results from mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes. We identified a Hispanic patient born of a consanguineous union who presented with immunodeficiency, partial albinism, hepatic dysfunction, hemophagocytosis, neurological impairment, nystagmus, and silvery hair indicative of Griscelli syndrome type 2 (GS2). We screened for point mutations, but only exons 2–6 of the patient’s DNA could be PCR-amplified. Whole genome analysis using the Illumina® 1M-Duo DNA Analysis BeadChip identified a homozygous deletion in the patient’s DNA. The exact breakpoints of the 47.5-kb deletion were identified as chr15q15-q21.1: g.53332432_53379990del (NCBI Build 37.1); the patient lacks the promoter and 5’UTR regions of RAB27A, thus confirming the diagnosis of GS2.

Vincent, Lisa M.; Gilbert, Fred; DiPace, Jennifer I.; Ciccone, Carla; Markello, Thomas C.; Jeong, Andrew; Dorward, Heidi; Westbroek, Wendy; Gahl, William A.; Bussel, James B.; Huizing, Marjan

2010-01-01

285

Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen syndrome: evidence for a common mechanism of chromosome breakage  

Microsoft Academic Search

Folate-sensitive fragile sites are associated with the expansion and hypermethylation of CCG-repeats. The fragile site in 11q23.3, FRA11B, has been shown to cause chromosome deletions in vivo, its expression being associated with Jacobsen (11q-) syndrome. However, the majority of Jacobsen deletions are distal to FRA11B and are not related to its expression. To test the hypothesis that other unidentified fragile

Christopher Jones; Roman Müllenbach; Paul Grossfeld; Rebecca Auer; Remi Favier; Ken Chien; Michael James; Alan Tunnacliffe; Finbarr Cotter

2000-01-01

286

Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome  

PubMed Central

The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome.

Souza, Josiane; Faucz, Fabio; Sotomaior, Vanessa; Filho, Aguinaldo Bonalumi; Rosenfeld, Jill; Raskin, Salmo

2011-01-01

287

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.

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

288

Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome  

PubMed Central

X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.

Koh, Ji Won; Kang, So Young; Kim, Gu Hwan; Yoo, Han Wook

2013-01-01

289

Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome  

PubMed Central

Background Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established. Design We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells. Results Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500?000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions. Conclusions The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS.

Bondy, Carolyn; Bakalov, Vladimir K; Cheng, Clara; Olivieri, Laura; Rosing, Douglas R; Arai, Andrew E

2013-01-01

290

Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12  

SciTech Connect

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome. 29 refs., 4 figs., 1 tab.

Rand, E.B.; Piccoli, D.A.; Spinner, N.B. [Univ. of Pennsylvania, Philadelphia, PA (United States)] [and others

1995-11-01

291

Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12.  

PubMed Central

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome. Images Figure 2 Figure 3

Rand, E B; Spinner, N B; Piccoli, D A; Whitington, P F; Taub, R

1995-01-01

292

CHILD Syndrome Caused by a Deletion of Exons 6–8 of the NSDHL Gene  

Microsoft Academic Search

The X-linked dominant CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is a rare developmental defect characterized by a strictly lateralized inflammatory nevus. In the majority of cases, the right side of the body is affected. Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys. We describe a case of CHILD syndrome involving the

C. A. Kim; A. König; D. R. Bertola; L. M. J. Albano; G. J. F. Gattás; D. Bornholdt; L. Leveleki; R. Happle; K.-H. Grzeschik

2005-01-01

293

Association of a mosaic chromosomal 22q 11 deletion with hypoplastic left heart syndrome  

Microsoft Academic Search

The atypical presentation of CATCH 22 raises several important concerns. First, in this patient, as in others, the heart defects were found in association with subtle facial abnormalities but with few of the other criteria normally seen in CATCH 22.3 This association alone may be sufficient to raise suspicion that an interstitial 22q11 deletion may be present. Second, the incidence

Michael W. Consevage; James R. Seip; Deborah A. Belchis; Abby T. Davis; Barry G. Baylen; Peter K. Rogan

1996-01-01

294

Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities  

Microsoft Academic Search

Background: Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2–29% because of different inclusion criteria.Methods: This study presents data compiled from 11 688 cases referred for subtelomere FISH testing in

J B Ravnan; J H Tepperberg; P Papenhausen; A N Lamb; J Hedrick; D Eash; D H Ledbetter; C L Martin

2006-01-01

295

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.

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

296

Trichorhinophalangeal syndrome type II without the chromosome 8 deletion that resembled metachondromatosis.  

PubMed

We describe a 5-year-old girl with features resembling Trichorhinophalangeal syndrome, type I (sparse scalp hair, bushy eyebrows, bulbous nose, long philtrum, cone-shaped epiphyses, clinobrachydactyly, epiphyseal changes in the femoral head and short stature), and appendicular exostoses similar to trichorhinophalangeal syndrome, type II. However, despite physical resemblance to the trichorhinophalangeal syndrome variants, cytological analysis showed a structurally normal chromosome 8 and no mental deficiency was apparent. In addition, morphological congruities between multiple exostoses and metachondromatosis was indicated from radiographic findings. PMID:17688470

Kikuchi, Noriaki; Ogino, Toshihiko; Kashiwa, Hideo; Muragaki, Yasuteru

2007-09-01

297

Multi-exon out of frame deletion of the FBN1 gene leading to a severe juvenile onset cardiovascular phenotype in Marfan syndrome  

Microsoft Academic Search

Marfan syndrome is caused by mutations in fibrillin-1, a large gene spanning ?200 kb of genomic DNA on chromosome 15q21. So far, more than 600 different mutations have been identified, accounting for 60–90% of all Marfan syndrome cases, the vast majority being single nucleotide exchanges as well as small deletions and insertions. Only four major rearrangements have been described in the

Krishna Kumar Singh; Diana Elligsen; Rüdiger Liersch; Stefanie Schubert; Brigitte Pabst; Mine Arslan-Kirchner; Jörg Schmidtke

2007-01-01

298

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome  

Microsoft Academic Search

Potocki–Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)]. The clinical features of PSS can include developmental delay, mental retardation, multiple exostoses, parietal foramina, enlarged anterior fontanel, minor craniofacial anomalies, ophthalmologic anomalies, and genital abnormalities in males. We constructed a natural panel of 11p11.2–p13

Keiko Wakui; Giuliana Gregato; Blake C Ballif; Caron D Glotzbach; Kristen A Bailey; Pao-Lin Kuo; Whui-Chen Sue; Leslie J Sheffield; Mira Irons; Enrique G Gomez; Jacqueline T Hecht; Lorraine Potocki; Lisa G Shaffer

2005-01-01

299

Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population  

Microsoft Academic Search

Rubinstein-Taybi syndrome (RTS) is a well delineated multiple congenital anomaly syndrome characterised by mental retardation, broad thumbs and toes, short stature, and specific facial features. The recent localisation of the disorder to 16p13.3 and subsequent identification of a submicroscopic deletion of this region in RTS patients led us to screen a large cohort of affected subjects using the RT1 probe.

R Wallerstein; C E Anderson; B Hay; P Gupta; L Gibas; K Ansari; F S Cowchock; V Weinblatt; C Reid; A Levitas; L Jackson

1997-01-01

300

Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior  

Microsoft Academic Search

Coffin–Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It\\u000a is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have\\u000a shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2\\u000a deficiency and skeletal abnormalities

R. Poirier; S. Jacquot; C. Vaillend; A. A. Soutthiphong; M. Libbey; S. Davis; S. Laroche; A. Hanauer; H. Welzl; H.-P. Lipp; D. P. Wolfer

2007-01-01

301

Microarray analysis of unbalanced translocation in Wolf-Hirschhorn syndrome.  

PubMed

Wolf-Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3, which is characterized by growth delay, mild-to-severe mental retardation, hypotonia, facial dysmorphisms and shows extensive phenotypic variability include feeding difficulties, epilepsy and congenital anomalies. Variation in the size of the deletion involving chromosome region 4p16.3 may explain the clinical variation. However, previous studies indicate that duplication for another chromosome region due to an unbalanced translocation elucidate approximately 40-45% WHS patients. Therefore, we used whole genomic cytogenetics array to analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize the exact subtelomeric aberration region of one patient with developmental delay and several facial characteristics reminiscent Wolf-Hirschhorn syndrome. Here we report that our patient had 3.7 Mb deletion at the 4p16.2 and 6.8 Mb duplication at 8p23.1 resulted from the unbalanced translocations der(4)t(4;8)(p16.2;p23.1). We confirmed that our patient with monosomy 4p16.2 which is consistent with Wolf-Hirschhorn syndrome and trisomy 8p23.1. The combination of the 4p deletion with 8p partial trisomy explains the complex phenotype presented by our patient. PMID:23782367

Dai, Ying; Yang, Jing; Chen, Yuanyuan; Bao, Liming; Cheng, Qian

2013-06-01

302

Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome  

Microsoft Academic Search

Background A 5-year-old year girl with a medical history of mental retardation, physical abnormalities and a known interstitial deletion of chromosome 9q22–q32 presented with a palpable suprapubic mass. During ultrasound investigation, a left renal mass was also detected. The patient underwent surgical removal of both neoplasms, which were diagnosed as a rhabdomyosarcoma and a Wilms tumor. Seven years later, she

Mariana M Cajaiba; Allen E Bale; Mayra Alvarez-Franco; Joseph McNamara; Miguel Reyes-Múgica

2006-01-01

303

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p.  

PubMed

We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198?kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests. PMID:23511928

Gurrieri, Fiorella; Zollino, Marcella; Oliva, Antonio; Pascali, Vincenzo; Orteschi, Daniela; Pietrobono, Roberta; Camporeale, Antonella; Coll Vidal, Monica; Partemi, Sara; Brugada, Ramon; Bellocci, Fulvio; Neri, Giovanni

2013-09-01

304

An 11p15 Imprinting Centre Region 2 Deletion in a Family with Beckwith Wiedemann Syndrome Provides Insights into Imprinting Control at CDKN1C  

PubMed Central

We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall.

Algar, Elizabeth; Dagar, Vinod; Sebaj, Menka; Pachter, Nicholas

2011-01-01

305

Reduced Fractional Anisotropy and Axial Diffusivity in White Matter in 22q11.2 Deletion Syndrome: A Pilot Study  

PubMed Central

Individuals with 22q11.2 deletion syndrome (22q11.2DS) evince a 30% incidence of schizophrenia. We compared the white matter (WM) of 22q11.2DS patients without schizophrenia to a group matched healthy controls using Tract-Based-Spatial-Statistics (TBSS). We found localized reduction of Fractional Anisotropy (FA) and Axial Diffusivity (AD; measure of axonal integrity) in WM underlying the left parietal lobe. No changes in Radial Diffusivity (RD; measure of myelin integrity) were observed. Of note, studies in chronic schizophrenia patients report reduced FA, no changes in AD, and increases in RD in WM. Our findings suggest different WM microstructure in 22q11.2DS than in patients with schizophrenia.

Kikinis, Z.; Asami, T.; Bouix, S.; Finn, C. T.; Ballinger, T.; Tworog-Dube, E.; Kucherlapati, R.; Kikinis, R.; Shenton, M. E.; Kubicki, M.

2012-01-01

306

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.

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

2001-01-01

307

Isochromosome 15q of maternal origin in two Prader-Willi syndrome patients previously diagnosed erroneously as cytogenetic deletions  

SciTech Connect

Since a previous report on two Prader-Willi syndrome (PWS) patients with t(15q;15q) was erroneous, the authors report new data and a corrected interpretation. Reexamination of the parental origin of their t(15q;15q) using polymorphic DNA markers that are mapped to various regions of 15q documented no molecular deletions at the 15q11-q13 region in either patient. Both patients were homozygous at all loci examined and their haplotypes on 15q coincided with one of those in their respective mothers. These results indicate that the presumed t(15q;15q) in each patient was actually an isochromosome 15q producing maternal uniparental disomy, consistent with genomic imprinting at the PWS locus. 30 refs., 1 fig., 3 tabs.

Saitoh, Shinji; Niikawa, Norio [Nagasaki Univ. School of Medicine (Japan); Mutirangura, A.; Kuwano, A.; Ledbetter, D.H. [Baylor College of Medicine, Houston, TX (United States)

1994-03-01

308

Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome.  

PubMed

Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenergic markers in 67 adults with 22q11DS. Levels of serotonin and the catecholamine metabolite homovanillic acid were significantly lower in the 22q11DS subjects compared to healthy controls. Within the 22q11DS group, levels of dopamine, homovanillic acid, norepinephrine, vanillyl mandelic acid and serotonin positively correlated with Full Scale Intelligence Quotient scores. Our results suggest that cognitive deficits in 22q11DS are associated with abnormal function of several neurotransmitters. PMID:24713114

Evers, Laurens J M; Curfs, Leopold M G; Bakker, Jaap A; Boot, Erik; da Silva Alves, Fabiana; Abeling, Nico; Bierau, Jörgen; Drukker, Marjan; van Amelsvoort, Therese A M J

2014-08-01

309

A New Account of the Neurocognitive Foundations of Impairments in Space, Time, and Number Processing in Children with Chromosome 22q11.2 Deletion Syndrome  

ERIC Educational Resources Information Center

In this article, I present an updated account that attempts to explain, in cognitive processing and neural terms, the nonverbal intellectual impairments experienced by most children with deletions of chromosome 22q11.2. Specifically, I propose that this genetic syndrome leads to early developmental changes in the structure and function of clearly…

Simon, Tony J.

2008-01-01

310

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

311

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

312

A 4 Mb cryptic deletion associated with inv(8)(q13.1q24.11) in a patient with trichorhinophalangeal syndrome type I.  

PubMed

We report on an 11 year old girl with trichorhinophalangeal syndrome type I (TRPS1), postaxial polydactyly of the fingers, and a de novo paracentric inversion on the long arm of chromosome 8 involving bands q13.1 and q24.11. Molecular analysis using FISH and polymorphic DNA markers detected an approximately 4 Mb, cytogenetically unidentified deletion occurring between two STSs markers, AFMB331YA9 and D8S1200, around the region of the distal inversion breakpoint. Although the deletion is large, mental retardation was not present in the patient. This is the first report of a cryptic deletion in a TRPS1 patient, both ends of which were analysed at the molecular level. The data obtained are useful for defining the location of the putative mental retardation gene(s) in TRPS1 and Langer-Giedion syndrome (TRPS2), as well as a locus for postaxial polydactyly. PMID:9138161

Sasaki, T; Tonoki, H; Soejima, H; Niikawa, N

1997-04-01

313

Pure distal 11q deletion without additional genomic imbalances in a female infant with Jacobsen syndrome and a de novo unbalanced reciprocal translocation.  

PubMed

We report a neonate with pure deletion of distal 11q (11q23.3-->qter) and Jacobsen syndrome. The patient had growth restriction, petechiae, thrombocytopenia, dilation of renal pelvis, congenital heart defects, and seizures. Array comparative genomic hybridization revealed a 15.8-Mb deletion from 11q23.3 to 11q25 without genomic imbalances in other chromosomes. Cytogenetic analysis revealed a karyotype of 46,XX,der(7)(7pter-->7q32),der(11)(11pter--> 11q23.3::7q32-->7qter). The parental karyotypes were normal. This is the first report of pure distal 11q deletion without additional genomic imbalances in a patient with Jacobsen syndrome and a de novo unbalanced reciprocal translocation. PMID:22876581

Chen, C-P; Lin, S-P; Hsu, C-H; Chern, S-R; Su, J-W; Chen, Y-J; Pan, C-W; Wang, W

2012-01-01

314

Cohabitation of insulators and silencing elements in yeast subtelomeric regions.  

PubMed Central

In budding yeast, the telomeric DNA is flanked by a combination of two subtelomeric repetitive sequences, the X and Y' elements. We have investigated the influence of these sequences on telomeric silencing. The telomere-proximal portion of either X or Y' dampened silencing when located between the telomere and the reporter gene. These elements were named STARs, for subtelomeric anti-silencing regions. STARs can also counteract silencer-driven repression at the mating-type HML locus. When two STARs bracket a reporter gene, its expression is no longer influenced by surrounding silencing elements, although these are still active on a second reporter gene. In addition, an intervening STAR uncouples the silencing of neighboring genes. STARs thus display the hallmarks of insulators. Protection from silencing is recapitulated by multimerized oligonucleotides representing Tbf1p- and Reb1p-binding sites, as found in STARs. In contrast, sequences located more centromere proximal in X and Y' elements reinforce silencing. They can promote silencing downstream of an insulated expressed domain. Overall, our results suggest that the silencing emanating from telomeres can be propagated in a discontinuous manner via a series of subtelomeric relay elements.

Fourel, G; Revardel, E; Koering, C E; Gilson, E

1999-01-01

315

Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to Gabrb3  

PubMed Central

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m?/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m?/p+), but not paternal (m+/p?), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Jiang, Yong-hui; Pan, Yanzhen; Zhu, Li; Landa, Luis; Yoo, Jong; Spencer, Corinne; Lorenzo, Isabel; Brilliant, Murray; Noebels, Jeffrey; Beaudet, Arthur L.

2010-01-01

316

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

317

Y2 Receptor Deletion Attenuates the Type 2 Diabetic Syndrome of ob\\/ob Mice  

Microsoft Academic Search

Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, nota- bly energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in geneti- cally obese ob\\/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate

Amanda Sainsbury; Christoph Schwarzer; Michelle Couzens; Herbert Herzog

2002-01-01

318

Autistic Spectrum Disorders in Velo-Cardio Facial Syndrome (22q11.2 Deletion)  

ERIC Educational Resources Information Center

The extent to which the phenotype of children comorbid for velocardiofacial syndrome (VCFS) and autism spectrum disorders (ASD) differs from that of VCFS-only has not been studied. The sample consisted of 41 children (20 females) with VCFS, ranging in age from 6.5 years to 15.8 years. Eight children with VCFS met formal DSM-IV diagnostic criteria…

Antshel, Kevin M.; Aneja, Alka; Strunge, Leslie; Peebles, Jena; Fremont, Wanda P.; Stallone, Kimberly; AbdulSabur, Nuria; Higgins, Anne Marie; Shprintzen, Robert J.; Kates, Wendy R.

2007-01-01

319

Discussing the psychiatric manifestations of 22q11.2 deletion syndrome: an exploration of clinical practice among medical geneticists  

PubMed Central

Purpose The aim of this study was to determine the frequency with which medical geneticists discuss the psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS) with families in relation to the frequency with which they discuss the other manifestations of the syndrome and to explore relationships between discussion of these features and stigma toward psychiatric disorders. Methods We surveyed medical geneticists in the United States and Canada regarding the frequency with which they discuss various features of 22q11DS with families in the context of four clinical scenarios in which only the age of the patient at diagnosis differed. Respondents also completed a 20-item validated psychometric measure of stigma towards psychiatric disorders. Results 308/546 medical geneticists completed the survey (56% response rate). Psychiatric disorders were discussed significantly less often than other features of 22q11DS (p<0.0001), but psychiatric disorders were discussed significantly more often when the patient was ? 13 years old (p<0.0001), than when the patient was younger. Geneticists who discussed psychiatric disorders the least had significantly higher levels of stigma towards psychiatric disorders (p=0.007). Conclusion Psychiatric risks are less often discussed with families during childhood. Education for physicians to help reduce stigma towards psychiatric disorders (which may impede discussion of psychiatric disorders) may warrant exploration in this population.

Morris, Emily; Inglis, Angela; Friedman, Jan; Austin, Jehannine

2013-01-01

320

Neuropsychological profile of Italian children and adolescents with 22q11.2 deletion syndrome with and without intellectual disability.  

PubMed

As individuals with chromosome 22q11.2 deletion syndrome (22q11DS) show a wide range of IQs, intellectual heterogeneity could mask the neuropsychological profile of the syndrome. This study was designed to identify specific neuropsychological features of children and adolescents with 22q11DS by taking into account the possible source of variability deriving from intellectual disability (ID). First, we compared several neuropsychological domains involving linguistic, visual-motor/visual-perceptual and memory abilities in 34 children and adolescents with 22q11DS and 83 mental age-matched typically developing (TD) participants. Then, we selected participants with 22q11DS according to whether or not they had ID and compared their neuropsychological profiles with those of chronological age-matched TD controls. Although language and several aspects of memory have been found impaired only in children with 22q11DS with ID, deficits in visual-spatial abilities and visual-object short-term memory persist in participants without ID and might be considered a characteristic of 22q11DS, not just related to the presence of ID. On the basis of our findings, children and adolescents with 22q11DS cannot be considered as a single group with a homogeneous neuropsychological profile and must be studied in relation to their global intellectual abilities. PMID:21870177

Vicari, Stefano; Mantovan, Manuela; Addona, Francesca; Costanzo, Floriana; Verucci, Lorena; Menghini, Deny

2012-03-01

321

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

322

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

323

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

324

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13. 3  

Microsoft Academic Search

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color

M. H. Breuning; H. G. Dauwerse; G. Fugazza; J. J. Saris; L. Spruit; H. Winjnen; G. C. Beverstock; G. J. B. van Ommen; N. Tommerup; C. B. van der Hagen; Kiyoshi Imaizumi; Yoshikazu Kuroki; M. J. van den Boogaard; J. M. de Pater; R. C. M. Hennekam; E. C. M. Mariman; B. C. J. Hamel; H. Himmelbauer; A. M. Frischauf; R. L. Stallings

1993-01-01

325

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome.  

PubMed

Potocki-Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)]. The clinical features of PSS can include developmental delay, mental retardation, multiple exostoses, parietal foramina, enlarged anterior fontanel, minor craniofacial anomalies, ophthalmologic anomalies, and genital abnormalities in males. We constructed a natural panel of 11p11.2-p13 deletions using cell lines from 10 affected individuals, fluorescence in situ hybridization (FISH), microsatellite analyses, and array-based comparative genomic hybridization (array CGH). We then compared the deletion sizes and clinical features between affected individuals. The full spectrum of PSS manifests when deletions are at least 2.1 Mb in size, spanning from D11S1393 to D11S1385/D11S1319 (44.6-46.7 Mb from the 11p terminus) and encompassing EXT2, responsible for multiple exostoses, and ALX4, causing parietal foramina. Yet one subject with parietal foramina whose deletion does not include ALX4 indicates that ALX4 in this subject may be rendered functionally haploinsufficient by a position effect. Based on comparative deletion mapping of eight individuals with the full PSS syndrome including mental retardation and two PSS families with no mental retardation, at least one gene related to mental retardation is likely located between D11S554 and D11S1385/D11S1319, 45.6-46.7 Mb from the 11p terminus. PMID:15852040

Wakui, Keiko; Gregato, Giuliana; Ballif, Blake C; Glotzbach, Caron D; Bailey, Kristen A; Kuo, Pao-Lin; Sue, Whui-Chen; Sheffield, Leslie J; Irons, Mira; Gomez, Enrique G; Hecht, Jacqueline T; Potocki, Lorraine; Shaffer, Lisa G

2005-05-01

326

A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin  

PubMed Central

Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277–1180_1386+2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.

Borelli, Iolanda; Barberis, Marco A; Spina, Francesca; Cavalchini, Guido C Casalis; Vivanet, Caterina; Balestrino, Luisa; Micheletti, Monica; Allavena, Anna; Sala, Paola; Carcassi, Carlo; Pasini, Barbara

2013-01-01

327

The internet is parents' main source of information about psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS).  

PubMed

With advances in laboratory technology, an increasing number of potentially pathogenic CNVs is recognised. The phenotypic effects of some CNVs are well characterised, however, it remains unclear how much information reaches the parents of affected children and by what route. The 22q11.2 deletion syndrome (del22q11.2) is caused by the deletion of approximately 40 genes from the long arm of chromosome 22 and was first described in 1955 [1]. Our study reports the extent to which parents of an affected child are aware of the various manifestation of the condition and describes how they first learned about these potential problems. PMID:23707654

van den Bree, Marianne B M; Miller, Gregory; Mansell, Elizabeth; Thapar, Anita; Flinter, Frances; Owen, Michael J

2013-08-01

328

Prenatal findings in a fetus with contiguous gene syndrome caused by deletion of Xp22.3 that includes locus for X-linked recessive type of chondrodysplasia punctata (CDPX1).  

PubMed

The X-linked recessive type of chondrodysplasia punctata (CDPX1) is a skeletal disorder that is characterized by stippled calcification at an epiphyseal nucleus and the surrounding soft tissue, short stature and an unusual face because of nasal hypoplasia. In most of the patients, this condition is noted after birth because of a characteristic face or respiratory problems. Here, we report a fetus with CDPX1. Two-dimensional ultrasound examination revealed unexplained polyhydramnios and a male fetus. Fetal biometry showed shortened long bones. Three-dimensional ultrasonography clearly demonstrated a hypoplastic nose with a depressed nasal bridge and contracture of wrists and fingers. Chromosome analysis of the amniotic fluid cells revealed the 46,Y,del(X)(p22.3) karyotype. Fluorescence in situ hybridization revealed a deletion of subtelomeric sequences at the Xpter and STS gene, but not a deletion of the KAL gene. The genomic copy number analysis demonstrated terminal deletion of 8.33 Mb that included SHOX, CSF2RA, XG, ARSE, NLGN4 and STS genes. We think that our case presents typical features of a fetus with this disorder and will be of great help in prenatal ultrasound diagnosis. PMID:20598055

Horikoshi, Tsuguhiro; Kikuchi, Akihiko; Tamaru, Shunsuke; Ono, Kyoko; Kita, Mariko; Takagi, Kimiyo; Miyashita, Susumu; Kawame, Hiroshi; Shimokawa, Osamu; Harada, Naoki

2010-06-01

329

An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome.  

PubMed

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1). PMID:11161813

Hilton, M J; Gutiérrez, L; Zhang, L; Moreno, P A; Reddy, M; Brown, N; Tan, Y; Hill, A; Wells, D E

2001-01-15

330

Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: Report of five families with a review of the literature  

SciTech Connect

The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (681%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22)(q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term {open_quotes}DiGeorge/velocardiofacial (DGNCF) syndrome{close_quotes} in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names. 41 refs., 2 figs., 2 tabs.

Leana-Cox, J.; Pangkanon, Suthipong; Eanet, K.R. [Univ. of Maryland School of Medicine, Baltimore, MD (United States)] [and others

1996-11-11

331

Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.  

PubMed

The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 Mb region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), which is responsible for loading Ca(2+) into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca(2+) load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8(+/-) mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia. PMID:23055483

Earls, Laurie R; Fricke, R Gaines; Yu, Jing; Berry, Raymond B; Baldwin, Lisa T; Zakharenko, Stanislav S

2012-10-10

332

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

333

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.  

PubMed

Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ~3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ~1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region. PMID:23756441

Fusco, Carmela; Micale, Lucia; Augello, Bartolomeo; Teresa Pellico, Maria; Menghini, Deny; Alfieri, Paolo; Cristina Digilio, Maria; Mandriani, Barbara; Carella, Massimo; Palumbo, Orazio; Vicari, Stefano; Merla, Giuseppe

2014-01-01

334

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.

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

2010-01-01

335

Complex Congenital Heart Disease in Unaffected Relatives of Adults With 22q11.2 Deletion Syndrome  

PubMed Central

The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first- to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS.

Swaby, Jodi-Ann M.; Silversides, Candice K.; Bekeschus, Sean C.; Piran, Sara; Oechslin, Erwin N.; Chow, Eva W. C.; Bassett, Anne S.

2011-01-01

336

A superfamily of variant genes encoded in the subtelomeric region of Plasmodium vivax  

Microsoft Academic Search

The malarial parasite Plasmodium vivax causes disease in humans, including chronic infections and recurrent relapses, but the course of infection is rarely fatal, unlike that caused by Plasmodium falciparum. To investigate differences in pathogenicity between P. vivax and P. falciparum, we have compared the subtelomeric domains in the DNA of these parasites. In P. falciparum, subtelomeric domains are conserved and

Hernando A. del Portillo; Carmen Fernandez-Becerra; Sharen Bowman; Karen Oliver; Martin Preuss; Cecilia P. Sanchez; Nick K. Schneider; Juan M. Villalobos; Marie-Adele Rajandream; David Harris; Luiz H. Pereira da Silva; Bart Barrell; Michael Lanzer

2001-01-01

337

Systematic Screening for Subtelomeric Anomalies in a Clinical Sample of Autism  

ERIC Educational Resources Information Center

High-resolution karyotyping detects cytogenetic anomalies in 5-10% of cases of autism. Karyotyping, however, may fail to detect abnormalities of chromosome subtelomeres, which are gene rich regions prone to anomalies. We assessed whether panels of FISH probes targeted for subtelomeres could detect abnormalities beyond those identified by…

Wassink, Thomas H.; Losh, Molly; Piven, Joseph; Sheffield, Val C.; Ashley, Elizabeth; Westin, Erik R.; Patil, Shivanand R.

2007-01-01

338

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

PubMed

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 14years 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-Reina, Julio; Jahanshad, Neda; Beaton, Elliott; Toga, Arthur W; Thompson, Paul M; Simon, Tony J

2013-11-01

339

Age-Related Changes in Subtelomeric Methylation in the Normal Japanese Population  

PubMed Central

Background The telomeres of somatic cells become shorter with individual aging. However, no significant change in subtelomeric methylation of somatic cells with aging has yet been reported. Methods Telomere lengths of the peripheral blood cells of 148 normal Japanese were analyzed by Southern blotting using methylation-sensitive and -insensitive isoschizomers. Results With aging, long telomeres decrease and short telomeres increase, and the contents of the telomeres with methylated subtelomere increase in long telomeres, thus leading us to postulate that telomeres with less methylated subtelomeres tend to become shortened faster. Conclusions A telomere length distribution analysis with methylation-sensitive and -insensitive isoschizomer seems to be a useful tool to assess the subtelomeric methylation status of the somatic cell population. The subtelomeric methylation of peripheral blood cells is also indicated to be an indicator for aging-associated genomic changes.

Guan, Jing Zhi; Oyama, Jun-ichi; Higuchi, Yoshihiro; Makino, Naoki

2009-01-01

340

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

Microsoft Academic Search

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

L. Potocki; L. G. Shaffer

1996-01-01

341

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

342

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

PubMed Central

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 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

Bartsch, O.; Wuyts, W.; Van Hul, W.; Hecht, J. T.; Meinecke, P.; Hogue, D.; Werner, W.; Zabel, B.; Hinkel, G. K.; Powell, C. M.; Shaffer, L. G.; Willems, P. J.

1996-01-01

343

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.

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, Silvere M.

2013-01-01

344

Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence: commonalities and differences between chromosomes.  

PubMed

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

2013-05-01

345

Partial trisomy of distal 8q derived from mother with mosaic 8q23.3----24.13 deletion, and relatively mild expression of trichorhinophalangeal syndrome I.  

PubMed

A 17-month-old girl with a partial trisomy of distal 8q derived from her mother, who has a mosaic 8q23.3----q24.13 deletion, was studied. Both showed a relatively mild phenotype of trichorhinophalangeal syndrome I. The karyotype of the proposita was designated as: 46,XX,-8,+der(8),inv ins(8;8)(p23.1;q24.13q23.3)mat. Her phenotype was considered similar to that of her mother despite the trisomies of distal 8q. She seems to be the first example of a partial trisomy of distal 8q derived from a parent with an interstitial deletion of a distal 8q segment and trichorhinophalangeal syndrome I. PMID:2722199

Naritomi, K; Hirayama, K

1989-05-01

346

Transient effect of anti-CD20 therapy in a child with 22q11.2 deletion syndrome and severe steroid refractory cytopenias: a case report.  

PubMed

We report on the development of steroid-refractory recurrent cytopenias in a child with 22q11.2 deletion syndrome. His first hematological complication was autoimmune hemolytic anemia at 3 months of age. Thereafter, he developed severe autoimmune cytopenias of all 3 hematological lineages with poor response to steroids and intravenous immunoglobulin. At the age of 2½ years, a course of anti-CD20 therapy (Rituximab) was given with transient hematological recovery. Because of persistent symptoms, bone marrow transplantation from a matched unrelated donor was performed. Although the data in the use of anti-CD20 therapy in children with 22q11.2 deletion syndrome and autoimmune cytopenias are limited, our experience suggests its potential benefit. PMID:23612383

Soldatou, Alexandra; Anastassiou, Theodora; Vougiouka, Olga; Goussetis, Evgenios; Kossiva, Lydia

2013-05-01

347

Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome.  

PubMed

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared with controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation. PMID:20074913

Beaton, Elliott A; Qin, Yufeng; Nguyen, Vy; Johnson, Joel; Pinter, Joseph D; Simon, Tony J

2010-02-28

348

Applicability of the nonverbal learning disability paradigm for children with 22q11.2 deletion syndrome.  

PubMed

Chromosome 22qll.2 deletion syndrome (22qllDS) is the most common microdeletion in humans. Nonverbal learning disability (NLD) has been used to describe the strengths and deficits of children with 22q11DS, but the applicability of the label for this population has seldom been systematically evaluated. The goal of the current study was to address how well the NLD diagnosis characterizes children and adolescents with 22q11DS. A total of 74 children and adolescents with 22q11DS were given neurocognitive, socioemotional, and academic assessments to measure aspects of NLD. Of the cohort, 20% met at least 7 of 9 assessed criteria for NLD; 25% showed verbal skills exceeding their nonverbal skills as assessed by an IQ test; and 24% showed the good rote verbal capacity commonly associated with NLD. Hypothesizing that if the entire cohort did not show consistent NLD characteristics, the descriptor might be more accurate for a distinct subgroup, the authors used latent class analysis to divide participants into three subgroups. However, the lines along which the groups broke out were more related to general functioning level than to NLD criteria. All three groups showed a heightened risk for psychiatric illness, highlighting the importance of careful mental health monitoring for all children with 22qllDS. PMID:22572413

Schoch, Kelly; Harrell, Waverly; Hooper, Stephen R; Ip, Edward H; Saldana, Santiago; Kwapil, Thomas R; Shashi, Vandana

2014-01-01

349

Cingulate gyral reductions are related to low executive functioning and psychotic symptoms in 22q 11.2 deletion syndrome.  

PubMed

A similar pattern of deficits in executive function and neuroanatomical abnormalities is shared between 22q 11.2 deletion syndrome (22q 11DS) and schizophrenia, suggesting that common cerebral alterations may lead to cognitive dysfunction and promote the appearance of psychotic symptoms in 22q 11DS individuals. Specifically, there is increasing evidence for involvement of the cingulate gyrus (CG) in executive dysfunction and the expression of positive symptoms in schizophrenia. The aim of our study is to examine CG morphology in a 22q 11DS population and its potential role as a cerebral marker of executive dysfunction and the manifestation of psychotic symptoms. Using region of interest (ROI)-based analysis, we compared CG volumes from 58 children and adults affected by 22q 11DS with 64 healthy age- and gender-matched controls. After covarying for total cranium grey matter and age, a bilateral reduced CG grey matter volume, driven by a decrease in anterior CG cortex, was observed among 22q 11DS patients. Further post hoc analyses suggest correlations between right CG cortical reductions, low-executive functioning and the occurrence of psychotic symptoms. The CG structural abnormalities observed in 22q 11DS are consistent with previous reports in schizophrenic patients and are associated with pre-morbid cognitive impairments. The mechanisms by which these changes may modulate executive functioning and the expression of psychosis are discussed. PMID:18616958

Dufour, Federico; Schaer, Marie; Debbané, Martin; Farhoumand, Riaz; Glaser, Bronwyn; Eliez, Stephan

2008-10-01

350

Hypoventilation in REM sleep in a case of 17p11.2 deletion (Smith-Magenis syndrome).  

PubMed

We describe a 2-year-old baby affected by Smith-Magenis syndrome (SMS), due to 17p11.2 deletion, who presented repeated episodes of hemoglobin desaturation during REM sleep. The boy, aged 14 months, presented a phenotype characterized by psychomotor delay, right posterior plagiocephaly, telecanthus, strabismus, upslanting palpebral fissures, broad hypoplastic nasal bridge, short philtrum, deep ring shaped skin creases around the limbs, proximal syndactyly, bilateral hypoacusia. Polysomnographic (PSG) recording showed episodes of REM-related hypoventilation (hemoglobin desaturations without apneas or hypopneas). Sleep disorders are present in almost all the cases of SMS, but very few reports describe the sleep-related respiratory patterns. The finding of REM hypoventilation in SMS does not allow an unequivocal interpretation. It could reflect a subclinical restrictive respiratory impairment or, alternatively, an impairment of central respiratory control during REM sleep. In SMS children, respiratory abnormalities during sleep, and in particular during REM sleep, may cause sleep disruption, reduction of time spent in REM sleep, and daytime sleepiness. We therefore suggest that some sleep abnormalities described in SMS could be consequent to Sleep Disordered Breathing, and in particular to REM hypoventilation. Sleep studies in SMS should include the recording of respiratory parameters. PMID:20186811

Leoni, Chiara; Cesarini, Laura; Dittoni, Serena; Battaglia, Domenica; Novelli, Antonio; Bernardini, Laura; Losurdo, Anna; Vollono, Catello; Testani, Elisa; Della Marca, Giacomo; Zampino, Giuseppe

2010-03-01

351

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

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

352

Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome  

PubMed Central

The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here we report that a mouse model of 22q11DS, the Df(16)1/+ mouse, exhibits substantially enhanced short- and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory. These changes are evident in mature but not young animals. Electrophysiological, two-photon imaging and glutamate uncaging, and electron microscopic assays in acute brain slices showed that enhanced neurotransmitter release but not altered postsynaptic function or structure caused these changes. Enhanced neurotransmitter release in Df(16)1/+ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). SERCA inhibitors rescued synaptic phenotypes of Df(16)1/+ mice. Thus, presynaptic SERCA2 upregulation may be a pathogenic event contributing to the cognitive symptoms of 22q11DS.

Earls, Laurie R.; Bayazitov, lldar T.; Fricke, Robert G.; Berry, Raymond B.; Illingworth, Elizabeth; Mittleman, Guy; Zakharenko, Stanislav S.

2010-01-01

353

Expression analysis and protein localization of the human HPC-1/syntaxin 1A, a gene deleted in Williams syndrome.  

PubMed

The HPC-1/syntaxin 1A (STX1A) gene maps to the Williams syndrome (WS) commonly deleted region on chromosome 7q11.23 and encodes a protein implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. To assess the potential role of STX1A in the WS phenotype, we carried out expression studies at the RNA and protein levels, in fetal and adult human tissues. RNA in situ hybridization on human embryo sections showed strong STX1A expression in spinal cord and ganglia. However, in adulthood, this gene was preferentially expressed in brain, as shown by Northern blot and RT-PCR experiments. Marked expression levels were observed in cerebellum and cerebral cortex. The STX1A protein was prevalently distributed in the molecular layer of the cerebellar cortex. A qualitative and quantitative analysis using a specific anti-STX1A antibody did not disclose any significant difference among frontal, temporal, and occipital poles of the human adult cortex in the two hemispheres. This is the first study focused on STX1A expression in humans. Our results indicate that this gene is strongly expressed in cerebral areas involved in cognitive process, supporting a likely role in the neurological symptoms of WS. PMID:10644452

Botta, A; Sangiuolo, F; Calza, L; Giardino, L; Potenza, S; Novelli, G; Dallapiccola, B

1999-12-15

354

Increased incidence and size of cavum septum pellicidum in children with chromosome 22q11.2 deletion syndrome  

PubMed Central

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of cavum septum pellucidum (CSP) in children aged 7 to 14 years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared to controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation.

Beaton, Elliott A.; Qin, Yufeng; Nguyen, Vy; Johnson, Joel; Pinter, Joseph D.; Simon, Tony J.

2009-01-01

355

Visual scanpath abnormalities in 22q11.2 deletion syndrome: is this a face specific deficit?  

PubMed

People with 22q11.2 deletion syndrome (22q11DS) have deficits in face emotion recognition. However, it is not known whether this is a deficit specific to faces, or represents maladaptive information processing strategies to complex stimuli in general. This study examined the specificity of face emotion processing deficits in 22q11DS by exploring recognition accuracy and visual scanpath performance to a Faces task compared to a Weather Scene task. Seventeen adolescents with 22q11DS (11=females, age=17.4) and 18 healthy controls (11=females, age=17.7) participated in the study. People with 22q11DS displayed an overall impoverished scanning strategy to face and weather stimuli alike, resulting in poorer accuracy across all stimuli for the 22q11DS participants compared to controls. While the control subjects altered their information processing in response to faces, a similar change was not present in the 22q11DS group indicating different visual scanpath strategies to identify category within each of the tasks, of which faces appear to represent a particularly difficult subcategory. To conclude, while this study indicates that people with 22q11DS have a general visual processing deficit, the lack of strategic change between tasks suggest that the 22q11DS group did not adapt to the change in stimuli content as well as the controls, indicative of cognitive inflexibility rather than a face specific deficit. PMID:21831452

McCabe, Kathryn; Rich, Dominique; Loughland, Carmel Maree; Schall, Ulrich; Campbell, Linda Elisabet

2011-09-30

356

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.

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

357

Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK  

PubMed Central

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. In recent years, causative mutations have been identified in atleast 15 genes encoding proteins of the neuromuscular junction. Mutations in MUSK are known as a very rare genetic cause of CMS and have been described in only three families, world-wide. Consequently, the knowledge about efficient drug therapy is very limited. We identified a novel missense mutation (p.Asp38Glu) heteroallelic to a genomic deletion affecting exons 2–3 of MUSK as cause of a limb-girdle CMS in two brothers of Turkish origin. Clinical symptoms included fatigable limb weakness from early childhood on. Upon diagnosis of a MUSK-related CMS at the age of 16 and 13 years, respectively, treatment with salbutamol was initiated leading to an impressive improvement of clinical symptoms, while treatment with esterase inhibitors did not show any benefit. Our findings highlight the importance of a molecular diagnosis in CMS and demonstrate considerable similarities between patients with MUSK and DOK7-related CMS in terms of clinical phenotype and treatment options.

Gallenmuller, Constanze; Muller-Felber, Wolfgang; Dusl, Marina; Stucka, Rolf; Guergueltcheva, Velina; Blaschek, Astrid; von der Hagen, Maja; Huebner, Angela; Muller, Juliane S.; Lochmuller, Hanns; Abicht, Angela

2014-01-01

358

Analysis of the efficacy of lenalidomide in patients with intermediate-1 risk myelodysplastic syndrome without 5q deletion  

PubMed Central

The aim of this study was to evaluate the efficacy and adverse effects of lenalidomide in the treatment of intermediate-1 risk non-5q deletion [non-del (5q)] myelodysplastic syndrome (MDS). A total of 30 patients with MDS were classified through G-banding chromosome karyotype analysis and fluorescence in situ hybridization (FISH). According to the International Prognostic Scoring System scores, among the 30 patients, 23 and seven cases had scores of 0.5 and 1.0, respectively. Lenalidomide (Revlimid®), 10 mg/day) was administered for 21 days every 28 days. All 30 cases were treated with lenalidomide for at least three cycles, including 20 cases with four cycles. The patients did not require erythropoietin, cyclosporine or iron chelation treatments. Statistical analysis was performed using SPSS statistical software version 13.0, and comparisons among groups were conducted using a t-test. The efficacy of lenalidomide was demonstrated in patients with intermediate-1 risk non-del (5q) MDS. Peripheral blood cell counts were improved following treatment, and absolute neutrophil, haemoglobin and platelet counts increased following 2–4 cycles of treatment. All patients became stable having undergone three cycles of treatment; however, 17 patients with chromosomal abnormalities had no cytogenetic response to the treatment, as confirmed through the FISH test. Patients with intermediate-1 risk non-del (5q) MDS treated with lenalidomide did not achieve complete haematological remission, although they demonstrated haematological improvement.

YANG, YAN; GAO, SUJUN; FAN, HONGQIONG; LIN, HAI; LI, WEI; WANG, JUAN

2013-01-01

359

Applicability of the Nonverbal Learning Disability Paradigm for Children With 22q11.2 Deletion Syndrome  

PubMed Central

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. Nonverbal learning disability (NLD) has been used to describe the strengths and deficits of children with 22q11DS, but the applicability of the label for this population has seldom been systematically evaluated. The goal of the current study was to address how well the NLD diagnosis characterizes children and adolescents with 22q11DS. A total of 74 children and adolescents with 22q11DS were given neurocognitive, socioemotional, and academic assessments to measure aspects of NLD. Of the cohort, 20% met at least 7 of 9 assessed criteria for NLD; 25% showed verbal skills exceeding their nonverbal skills as assessed by an IQ test; and 24% showed the good rote verbal capacity commonly associated with NLD. Hypothesizing that if the entire cohort did not show consistent NLD characteristics, the descriptor might be more accurate for a distinct subgroup, the authors used latent class analysis to divide participants into three subgroups. However, the lines along which the groups broke out were more related to general functioning level than to NLD criteria. All three groups showed a heightened risk for psychiatric illness, highlighting the importance of careful mental health monitoring for all children with 22q11DS.

Schoch, Kelly; Harrell, Waverly; Hooper, Stephen R.; Ip, Edward H.; Saldana, Santiago; Kwapil, Thomas R.; Shashi, Vandana

2014-01-01

360

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: a longitudinal study.  

PubMed

The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenia-like psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescence-early adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population. PMID:17804201

Gothelf, Doron; Penniman, Lauren; Gu, Eugene; Eliez, Stephan; Reiss, Allan L

2007-11-01

361

Developmental Trajectories of Brain Structure in Adolescents with 22q11.2 Deletion Syndrome: A Longitudinal Study  

PubMed Central

The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenia-like psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescence-early adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population.

Gothelf, Doron; Penniman, Lauren; Gu, Eugene; Eliez, Stephan; Reiss, Allan L.

2008-01-01

362

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

PubMed

A quantitative long-term fluid consumption and fluid-licking assay was performed in two mouse models with either an ?2?Mb genomic deletion, Df(11)17, or the reciprocal duplication copy number variation (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 alterations 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 versus deletion showed longer versus shorter intervals between visits to the waterspout, generated more versus less licks per visit and had higher versus 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 behavioral 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

2012-11-01

363

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.

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

2012-01-01

364

Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader-Willi/Angelman syndromes.  

PubMed

Approximately 70% of patients with Prader-Willi syndrome or Angelman syndrome have a similar sized de novo deletion of 3-4 Mb in the proximal region of 15q. The distal breakpoints appear to cluster between the P gene (OCA2) and D15S24, whereas two deletion breakpoint clusters have been identified on the proximal side (one centromeric to D15S541 and one between D15S541 and D15S9). Based on the identification of a gene family in 15q11-->q13 (MN7, D15F37), we have previously proposed that the presence of multiple copies of this sequence may be related to the instability of this region. Using fluorescence in situ hybridization and YAC mapping, we have found that at least one D15F37 locus is centromeric to D15S9 and at least two are between OCA2 and D15S24. As determined by cDNA cloning and sequence analysis, each of the individual loci is expressed. The close proximity of the D15F37 loci and the deletion breakpoints suggests that the common deletions arise by unequal crossover events at or near these loci. PMID:9730612

Buiting, K; Gross, S; Ji, Y; Senger, G; Nicholls, R D; Horsthemke, B

1998-01-01

365

Targeted Deletion of the Gene Encoding the La Autoantigen (Sj?gren'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.

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

366

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis, array comparative genomic hybridization characterization using uncultured amniocytes and literature review.  

PubMed

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot. PMID:23791650

Chen, Chih-Ping; Huang, Jian-Pei; Chen, Yi-Yung; Chern, Schu-Rern; Wu, Peih-Shan; Su, Jun-Wei; Chen, Yu-Ting; Chen, Wen-Lin; Wang, Wayseen

2013-09-15

367

Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings  

PubMed Central

Background Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning. Methods Thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR?

2012-01-01

368

Chromosome 2p15p16.1 microdeletion syndrome: 2.5 Mb deletion in a patient with renal anomalies, intractable seizures and a choledochal cyst.  

PubMed

Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.0 array we identified a de novo interstitial deletion on the short arm of chromosome 2, spanning approximately 2.5 Mb in the cytogenetic band position 2p15p16.1, in a female infant with characteristic features of 2p15p16.1 deletion syndrome including severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect. We further redefined the previously reported critical region, supporting the presence of a newly recognized microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 1.1 Mb segment of the 2p15p16.1 region. PMID:22579565

Hucthagowder, Vishwanathan; Liu, Ta-Chiang; Paciorkowski, Alex R; Thio, Liu Lin; Keller, Martin S; Anderson, Christopher D; Herman, Thomas; Dehner, Louis P; Grange, Dorothy K; Kulkarni, Shashikant

2012-01-01

369

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome.  

PubMed

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400?kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder. PMID:23963300

Andersen, Erica F; Carey, John C; Earl, Dawn L; Corzo, Deyanira; Suttie, Michael; Hammond, Peter; South, Sarah T

2014-04-01

370

Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an approximately 5 Mb deletion del(11)(q24.3).  

PubMed

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between approximately 7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4-year-old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole-genome oligonucleotide array CGH analyses, we identified an approximately 5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located approximately 6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS. PMID:18792974

Bernaciak, Joanna; Szcza?uba, Krzysztof; Derwi?ska, Katarzyna; Wi?niowiecka-Kowalnik, Barbara; Bocian, Ewa; Sasiadek, Maria Ma?gorzata; Makowska, Izabela; Stankiewicz, Pawe?; Smigiel, Robert

2008-10-01

371

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

372

Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein–Taybi syndrome  

Microsoft Academic Search

Rubinstein–Taybi syndrome (RSTS) is a well-known autosomal dominant mental retardation syndrome with typical facial and skeletal abnormalities. Previously, we have reported two patients presenting with RSTS and additional clinical features including failure to thrive, seizures, and intractable infections (Bartsch et al. in Eur J Hum Genet 7:748–756, 1999). Recently we identified a third patient with this condition, termed here severe

Oliver Bartsch; Sasan Rasi; Alicia Delicado; Sarah Dyack; Luitgard M. Neumann; Eva Seemanová; Marianne Volleth; Thomas Haaf; Vera M. Kalscheuer

2006-01-01

373

DDX11L: a novel transcript family emerging from human subtelomeric regions  

PubMed Central

Background The subtelomeric regions of human chromosomes exhibit an extraordinary plasticity. To date, due to the high GC content and to the presence of telomeric repeats, the subtelomeric sequences are underrepresented in the genomic libraries and consequently their sequences are incomplete in the finished human genome sequence, and still much remains to be learned about subtelomere organization, evolution and function. Indeed, only in recent years, several studies have disclosed, within human subtelomeres, novel gene family members. Results During a project aimed to analyze genes located in the telomeric region of the long arm of the human X chromosome, we have identified a novel transcript family, DDX11L, members of which map to 1pter, 2q13/14.1, 2qter, 3qter, 6pter, 9pter/9qter, 11pter, 12pter, 15qter, 16pter, 17pter, 19pter, 20pter/20qter, Xpter/Xqter and Yqter. Furthermore, we partially sequenced the underrepresented subtelomeres of human chromosomes showing a common evolutionary origin. Conclusion Our data indicate that an ancestral gene, originated as a rearranged portion of the primate DDX11 gene, and propagated along many subtelomeric locations, is emerging within subtelomeres of human chromosomes, defining a novel gene family. These findings support the possibility that the high plasticity of these regions, sites of DNA exchange among different chromosomes, could trigger the emergence of new genes.

Costa, Valerio; Casamassimi, Amelia; Roberto, Roberta; Gianfrancesco, Fernando; Matarazzo, Maria R; D'Urso, Michele; D'Esposito, Maurizio; Rocchi, Mariano; Ciccodicola, Alfredo

2009-01-01

374

Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300).  

PubMed Central

The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues. Images

Rotig, A; Cormier, V; Chatelain, P; Francois, R; Saudubray, J M; Rustin, P; Munnich, A

1993-01-01

375

In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome.  

PubMed

Using high-resolution molecular karyotyping with SNP arrays to identify candidate genes for etiologically unexplained intellectual disability, we identified a 32-kb de novo in-frame deletion of the C-terminal helicase domain of the SMARCA2 gene in a patient with severe intellectual disability, epilepsy, sparse hair, prominent joints, and distinct facial anomalies. Sequencing of the gene in patients with a similar phenotype revealed de novo missense mutations in this domain in 2 further patients, pointing to a crucial role of the SMARCA2 C-terminal helicase domain. The clinical features observed in all 3 patients are typical of Nicolaides-Baraitser syndrome, an only rarely reported syndrome with mainly moderate to severe intellectual disability. Notably, one of our patients with a p.Gly1132Asp mutation showed typical morphological features but an exceptional good development with borderline overall IQ and learning difficulties, thus expanding the phenotypic spectrum of Nicolaides-Baraitser syndrome. PMID:22822383

Wolff, D; Endele, S; Azzarello-Burri, S; Hoyer, J; Zweier, M; Schanze, I; Schmitt, B; Rauch, A; Reis, A; Zweier, C

2012-04-01

376

Atypical Developmental Trajectory of Functionally Significant Cortical Areas in Children with Chromosome 22q11.2 Deletion Syndrome  

PubMed Central

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.

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

2011-01-01

377

Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.  

PubMed

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. PMID:22495892

Burkitt-Wright, Emma M M; Bradley, Lisa; Shorto, Jennifer; McConnell, Vivienne P M; Gannon, Caroline; Firth, Helen V; Park, Soo-Mi; D'Amore, Angela; Munyard, Paul F; Turnpenny, Peter D; Charlton, Amanda; Wilson, Meredith; Kerr, Bronwyn

2012-05-01

378

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.

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

2010-01-01

379

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

PubMed

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

2014-02-01

380

Whole-genome SNP association in the horse: identification of a deletion in myosin Va responsible for Lavender Foal Syndrome.  

PubMed

Lavender Foal Syndrome (LFS) is a lethal inherited disease of horses with a suspected autosomal recessive mode of inheritance. LFS has been primarily diagnosed in a subgroup of the Arabian breed, the Egyptian Arabian horse. The condition is characterized by multiple neurological abnormalities and a dilute coat color. Candidate genes based on comparative phenotypes in mice and humans include the ras-associated protein RAB27a (RAB27A) and myosin Va (MYO5A). Here we report mapping of the locus responsible for LFS using a small set of 36 horses segregating for LFS. These horses were genotyped using a newly available single nucleotide polymorphism (SNP) chip containing 56,402 discriminatory elements. The whole genome scan identified an associated region containing these two functional candidate genes. Exon sequencing of the MYO5A gene from an affected foal revealed a single base deletion in exon 30 that changes the reading frame and introduces a premature stop codon. A PCR-based Restriction Fragment Length Polymorphism (PCR-RFLP) assay was designed and used to investigate the frequency of the mutant gene. All affected horses tested were homozygous for this mutation. Heterozygous carriers were detected in high frequency in families segregating for this trait, and the frequency of carriers in unrelated Egyptian Arabians was 10.3%. The mapping and discovery of the LFS mutation represents the first successful use of whole-genome SNP scanning in the horse for any trait. The RFLP assay can be used to assist breeders in avoiding carrier-to-carrier matings and thus in preventing the birth of affected foals. PMID:20419149

Brooks, Samantha A; Gabreski, Nicole; Miller, Donald; Brisbin, Abra; Brown, Helen E; Streeter, Cassandra; Mezey, Jason; Cook, Deborah; Antczak, Douglas F

2010-04-01

381

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression.  

PubMed

The Nijmegen breakage syndrome (NBS1) gene was suggested as a prostate cancer susceptibility gene. This study was undertaken to determine, whether NBS1 expression is linked to clinically or molecularly relevant subgroups of prostate cancer. NBS1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. NBS1 expression was absent or only weakly detectable in benign prostate. In prostate cancers, NBS1 expression was found in 81.3% of interpretable tumors and was considered strong in 41.3% of cases. NBS1 upregulation was tightly linked to ERG-positive cancers (p?deletions revealed a strong NBS1 upregulation in PTEN-deleted cancers, while deletions of 3p13, 5q21 and 6q15 did not affect NBS1 expression. High NBS1 expression was linked to biochemical recurrence in ERG-negative and PTEN non-deleted cancers (p?deletion. The prognostic impact of NBS1 expression in ERG-negative, PTEN non-deleted cancers was dependent of the expression status of its interaction partner KPNA2. PMID:24510842

Grupp, Katharina; Boumesli, Rebecca; Tsourlakis, Maria Christina; Koop, Christina; Wilczak, Waldemar; Adam, Meike; Sauter, Guido; Simon, Ronald; Izbicki, Jakob Robert; Graefen, Markus; Huland, Hartwig; Steurer, Stefan; Schlomm, Thorsten; Minner, Sarah; Quaas, Alexander

2014-09-15

382

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

383

Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion.  

PubMed

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-hr melatonin secretion patterns in two independent SMS cohorts (US and 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 ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) 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

2009-07-01

384

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

PubMed Central

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.

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

2014-01-01

385

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