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A higher rare CNV burden in the genetic background potentially contributes to intellectual disability phenotypes in 22q11.2 deletion syndrome.

ABSTRACT: The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30-40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that it is a relatively rare disorder (1/2000-6000 in humans), limited research has shed light into the contribution of these second-site variants to the developmental pathogenesis that underlies 22q11DS. As CNVs throughout the genome might constitute such a genetic risk factor for variability in the 22q11DS phenotypes such as intellectual disability, we sought to determine if the overall burden of rare CNVs in the genetic background influenced the phenotypic variability. We analyzed CNV and clinical data from 66 individuals with 22q11DS, and found that 77% (51/66) of individuals with the 22q11DS also carry additional rare CNVs (<0.1% frequency). We observed several trends between CNV burden and phenotype, including that the burden of large rare CNVs (>200 Kb in size) was significantly higher in 22q11DS individuals with intellectual disability than with normal IQ. Our analysis shows that rare CNVs may contribute to intellectual disability 22q11DS, and further analysis on larger 22q11DS cohorts should be performed to confirm this correlation.

SUBMITTER: Jensen M

PROVIDER: S-EPMC6991138 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A higher rare CNV burden in the genetic background potentially contributes to intellectual disability phenotypes in 22q11.2 deletion syndrome.

Jensen Matthew M Kooy R Frank RF Simon Tony J TJ Reyniers Edwin E Girirajan Santhosh S Tassone Flora F

European journal of medical genetics 20171128 4

The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30-40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that i ...[more]

PMID: 29191496

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Project description:BACKGROUND:Intellectual disability (ID) is a complex condition that can impact multiple domains of development. The genetic contribution to ID's etiology is significant, with more than 100 implicated genes and loci currently identified. The majority of such variants are rare and de novo genetic mutations. METHODS:We have applied whole-genome microarray to identify large, rare, clinically relevant copy number variants (CNVs). We have applied well-established algorithms for variants call. Quantitative polymerase chain reaction (qPCR) was applied to validate the variants using three technical replicates for each family member. To assess whether the copy number variation was due to balanced translocation or mosaicism, we further conducted droplet digital PCR (ddPCR) on the whole family. We have, as well, applied "critical-exon" mapping, human developmental brain transcriptome, and a database of known associated neurodevelopmental disorder variants to identify candidate genes. RESULTS:Here we present two siblings who are both impacted by a large terminal duplication and a deletion. Whole-genome microarray revealed an 18.82 megabase (MB) duplication at terminal locus (7q34-q36.3) of chromosome 7 and a 3.90 MB deletion impacting the terminal locus (15q26.3) of chromosome 15. qPCR and ddPCR experiments confirmed the de novo origin of the variants and the co-occurrence of these two de novo events among the siblings, but their absence in both parents, implicates an unbalanced translocation that could have mal-segregated among the siblings or a possible germline mosaicism. These terminal events impact IGF1R, CNTNAP2, and DPP6, shown to be strongly associated with neurodevelopmental disorders. Detailed clinical examination of the siblings revealed the presence of both shared and distinct phenotypic features. CONCLUSIONS:This study identified two large rare terminal de novo events impacting two siblings. Further phenotypic investigation highlights that even in the presence of identical large high penetrant variants, spectrum of clinical features can be different between the siblings.

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A higher rare CNV burden in the genetic background potentially contributes to intellectual disability phenotypes in 22q11.2 deletion syndrome.

Publications

A higher rare CNV burden in the genetic background potentially contributes to intellectual disability phenotypes in 22q11.2 deletion syndrome.

Similar Datasets

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