Using whole-exome sequencing to identify inherited causes of autism.
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
Division of Genetics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA. timothy.yu@childrens.harvard.edu
Timothy W
TW
Yu
Maria H
MH
Chahrour
Michael E
ME
Coulter
Sarn
S
Jiralerspong
Kazuko
K
Okamura-Ikeda
Bulent
B
Ataman
Klaus
K
Schmitz-Abe
David A
DA
Harmin
Mazhar
M
Adli
Athar N
AN
Malik
Alissa M
AM
D'Gama
Elaine T
ET
Lim
Stephan J
SJ
Sanders
Ganesh H
GH
Mochida
Jennifer N
JN
Partlow
Christine M
CM
Sunu
Jillian M
JM
Felie
Jacqueline
J
Rodriguez
Ramzi H
RH
Nasir
Janice
J
Ware
Robert M
RM
Joseph
R Sean
RS
Hill
Benjamin Y
BY
Kwan
Muna
M
Al-Saffar
Nahit M
NM
Mukaddes
Asif
A
Hashmi
Soher
S
Balkhy
Generoso G
GG
Gascon
Fuki M
FM
Hisama
Elaine
E
LeClair
Annapurna
A
Poduri
Ozgur
O
Oner
Samira
S
Al-Saad
Sadika A
SA
Al-Awadi
Laila
L
Bastaki
Tawfeg
T
Ben-Omran
Ahmad S
AS
Teebi
Lihadh
L
Al-Gazali
Valsamma
V
Eapen
Christine R
CR
Stevens
Leonard
L
Rappaport
Stacey B
SB
Gabriel
Kyriacos
K
Markianos
Matthew W
MW
State
Michael E
ME
Greenberg
Hisaaki
H
Taniguchi
Nancy E
NE
Braverman
Eric M
EM
Morrow
Christopher A
CA
Walsh
D000293:Adolescent; D000818:Animals; D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D010375:Pedigree; D051381:Rats; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult