Molecular definition of the 22q11 deletions in Velo-Cardio-Facial Syndrome

Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/1995; 56(6):1391-403.
Source: PubMed


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.

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Available from: Robert Shprintzen, Oct 04, 2015
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    • "The 22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are known neurogenetic autosomal dominant syndromes, both caused by a microdeletion, 22q11.2DS in the long arm of chromosome 22 [1] and WS in the long arm of chromosome 7 (7q11.23) [2]. "
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    ABSTRACT: 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. 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. 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. Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.
    Journal of Neurodevelopmental Disorders 02/2014; 6(1):3. DOI:10.1186/1866-1955-6-3 · 3.27 Impact Factor
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    • "deletion syndrome (22q11DS), a rare neurogenetic condition associated with increased risk for schizophrenia (Murphy, 2005). 22q11DS is the most common interstitial deletion in humans (Scambler, 2000) and is characterized by a 3Mb microdeletion in the majority of cases (Morrow et al., 1995). About 60 genes are contained within the deleted segment, some of which have been associated with specific characteristics of the 22q11DS phenotype such as cardiac or palate malformations (e.g. "
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    ABSTRACT: The investigation of self-reflective processing during adolescence is relevant, as this period is characterized by deep reorganization of the self-concept. It may be the case that an atypical development of brain regions underlying self-reflective processing increases the risk for psychological disorders and impaired social functioning. In this study, we investigated the neural bases of self- and other-related processing in typically developing adolescents and youths with 22q11.2 deletion syndrome (22q11DS), a rare neurogenetic condition associated with difficulties in social interactions and increased risk for schizophrenia. The fMRI paradigm consisted in judging if a series of adjectives applied to the participant himself/herself (self), to his/her best friend or to a fictional character (Harry Potter). In control adolescents, we observed that self- and other-related processing elicited strong activation in cortical midline structures (CMS) when contrasted with a semantic baseline condition. 22q11DS exhibited hypoactivation in the CMS and the striatum during the processing of self-related information when compared to the control group. Finally, the hypoactivation in the anterior cingulate cortex was associated with the severity of prodromal positive symptoms of schizophrenia. The findings are discussed in a developmental framework and in light of their implication for the development of schizophrenia in this at-risk population.
    04/2012; 2(2):277-89. DOI:10.1016/j.dcn.2011.12.004
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    • "This small difference in size of the deletion was not expected to be detectable by the FISH. Hence, we may conclude that most of the negative studies on size using FISH [18,20,24-26] may not be correct. The difference in the size with the phenotypic discordance was observed with other microdeletion syndromes viz., Yq microdeletion [27], Wolf-Hirschhorn Syndrome [28], etc. "
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    ABSTRACT: We report on a pair of male monozygotic twins with 22q11.2 microdeletion, discordant phenotype and discordant deletion size. The second twin had findings suggestive of DiGeorge syndrome, while the first twin had milder anomalies without any cardiac malformation. The second twin had presented with intractable convulsion, cyanosis and cardiovascular failure in the fourth week of life and expired on the sixth week of life, whereas the first twin had some characteristic facial appearance with developmental delay but no other signs of the 22q11.2 microdeletion syndrome including cardiovascular malformation. The fluorescence in situ hybridization (FISH) analysis had shown a microdeletion on the chromosome 22q11.2 in both twins. The interphase FISH did not find any evidence for the mosaicism. The genomic DNA microarray analysis, using HumanCytoSNP-12 BeadChip (Illumina), was identical between the twins except different size of deletion of 22q11.2. The zygosity using HumanCytoSNP-12 BeadChip (Illumina) microarray analysis suggested monozygosity. This observation indicates that altered size of the deletion may be the underlying etiology for the discordance in phenotype in monozygotic twins. We think early post zygotic events (mitotic non-allelic homologous recombination) could have been played a role in the alteration of 22q11.2 deletion size and, thus phenotypic variability in the monozygotic twins.
    Molecular Cytogenetics 03/2012; 5(1):13. DOI:10.1186/1755-8166-5-13 · 2.14 Impact Factor
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