Open AccessExome sequencing of 85 Williams–Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior
Author(s) -
Kopp Nathan D.,
Parrish Phoebe C. R.,
Lugo Michael,
Dougherty Joseph D.,
Kozel Beth A.
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.429
Subject(s) - exome sequencing , genetics , autism spectrum disorder , autism , exome , williams syndrome , copy number variation , biology , haploinsufficiency , phenotype , cognition , gene , developmental psychology , psychology , genome , neuroscience
Background Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams–Beuren syndrome ( WS ). Of particular interest is the unusual social‐cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders ( ASD ) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD ‐like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. Method Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. Results We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNP s in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ 1B and GTF 2 IRD 1 . Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. Conclusions Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains.