Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

Bucan, Maja

Abrahams, Brett S

Wang, Kai

Glessner, Joseph T

Herman, Edward I

Sonnenblick, Lisa I

Alvarez Retuerto, Ana I

Imielinski, Marcin

Hadley, Dexter

Bradfield, Jonathan P

Kim, Cecilia

Gidaya, Nicole B

Lindquist, Ingrid

Hutman, Ted

Sigman, Marian

Kustanovich, Vlad

Lajonchere, Clara M

Singleton, Andrew

Kim, Junhyong

Wassink, Thomas H

McMahon, William M

Owley, Thomas

Sweeney, John A

Coon, Hilary

Nurnberger, John I

Li, Mingyao

Cantor, Rita M

Minshew, Nancy J

Sutcliffe, James S

Cook, Edwin H

Dawson, Geraldine

Buxbaum, Joseph D

Grant, Struan FA

Schellenberg, Gerard D

Geschwind, Daniel H

Hakonarson, Hakon

United States

2017-04-02T19:29:40Z

2017-04-02T19:29:40Z

2009-06

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

https://www.ncbi.nlm.nih.gov/pubmed/19557195

1553-7404

https://hdl.handle.net/10161/13928

eng

Public Library of Science (PLoS)

PLoS Genet

10.1371/journal.pgen.1000536

Adolescent

Autistic Disorder

Case-Control Studies

Cell Adhesion Molecules, Neuronal

Child

Child, Preschool

Cohort Studies

Exons

Female

Gene Dosage

Gene Duplication

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Male

Nerve Tissue Proteins

Pedigree

Sequence Deletion

Ubiquitin-Protein Ligases

Young Adult

Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

Journal article

Dawson, Geraldine|0000-0003-1410-2764

https://www.ncbi.nlm.nih.gov/pubmed/19557195

e1000536

6

Clinical Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Pediatrics

Psychiatry, Child & Family Mental Health and Developmental Neuroscience

Psychiatry & Behavioral Sciences

Sanford School of Public Policy

Sanford School of Public Policy - Secondary Group

School of Medicine

University Institutes and Centers

Published

5