TY - JOUR
T1 - Exome sequencing of 85 Williams–Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior
AU - Kopp, Nathan D.
AU - Parrish, Phoebe C.R.
AU - Lugo, Michael
AU - Dougherty, Joseph D.
AU - Kozel, Beth A.
N1 - Funding Information:
None of the authors have any conflicts of interest to report. We thank Drs. Natasha Marrus and John Constantino for helpful discussions of the SRS, and Dr. Don Conrad for discussion of association analyses. We acknowledge the McDonnell Genome Institute at Washington University who performed the exome sequencing performed in this study. NDK was supported by the Autism Science Foundation and the NSF (DGE‐1143954), This work was supported by the Children's Discovery Institute(MD‐II‐2013‐269 to JDD and BAK and CH‐FR‐2011‐169 to BAK) and the NIH (1R01MH107515‐01A1, 5R01HG008687‐02, 9R01MH 100027‐06 for JDD and HL006212‐01 for BAK). JDD is an investigator of the Brain and Behavior Research Foundation. BAK received funding for this project from the Heartland Genetic Services Collaborative. We also thank the Williams Syndrome Association, Dr. Barbara Pober for her help with recruitment, and the families who participated in this study.
Funding Information:
None of the authors have any conflicts of interest to report. We thank Drs. Natasha Marrus and John Constantino for helpful discussions of the SRS, and Dr. Don Conrad for discussion of association analyses. We acknowledge the McDonnell Genome Institute at Washington University who performed the exome sequencing performed in this study. NDK was supported by the Autism Science Foundation and the NSF (DGE-1143954), This work was supported by the Children's Discovery Institute(MD-II-2013-269 to JDD and BAK and CH-FR-2011-169 to BAK) and the NIH (1R01MH107515-01A1, 5R01HG008687-02, 9R01MH100027-06 for JDD and HL006212-01 for BAK). JDD is an investigator of the Brain and Behavior Research Foundation. BAK received funding for this project from the Heartland Genetic Services Collaborative. We also thank the Williams Syndrome Association, Dr. Barbara Pober for her help with recruitment, and the families who participated in this study.
Funding Information:
Children's Discovery Institute, Grant/ Award Number: MD-II-2013-269; National Science Foundation, Grant/Award Number: DGE-1143954; Autism Science Foundation; National Institutes of Health, Grant/Award Number: 1R01MH107515-01A1, 5R01HG008687-02, 9R01MH100027-06, HL006212-01
Publisher Copyright:
© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
PY - 2018/9
Y1 - 2018/9
N2 - 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 SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. 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.
AB - 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 SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. 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.
KW - Williams–Beuren syndrome
KW - autism spectrum disorder
KW - exome variation
KW - social responsiveness scale
UR - http://www.scopus.com/inward/record.url?scp=85050612554&partnerID=8YFLogxK
U2 - 10.1002/mgg3.429
DO - 10.1002/mgg3.429
M3 - Article
C2 - 30008175
AN - SCOPUS:85050612554
VL - 6
SP - 749
EP - 765
JO - Molecular Genetics and Genomic Medicine
JF - Molecular Genetics and Genomic Medicine
SN - 2324-9269
IS - 5
ER -