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Published online on July 25, 2007, 10.1073/pnas.0705803104
PNAS | July 31, 2007 | vol. 104 | no. 31 | 12831-12836
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BIOLOGICAL SCIENCES / GENETICS
A unified genetic theory for sporadic and inherited autism

Xiaoyue Zhao*, Anthony Leotta*, Vlad Kustanovich{dagger}, Clara Lajonchere{dagger}, Daniel H. Geschwind{ddagger}, Kiely Law§, Paul Law§, Shanping Qiu, Catherine Lord, Jonathan Sebat*, Kenny Ye||,**, and Michael Wigler*,**

*Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724; {dagger}Autism Genetic Resource Exchange, Cure Autism Now, 5455 Wilshire Boulevard, Suite 2250, Los Angeles, CA 90036; {ddagger}Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1769; §Department of Medical Informatics, and Interactive Autism Network, Kennedy Krieger Institute, Baltimore, MD 21205; University of Michigan Autism and Communication Disorders Center, 1111 East Catherine Street, Ann Arbor, MI 48109-2054; and ||Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461

Contributed by Michael Wigler, June 20, 2007 (received for review June 1, 2007)

Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.

human genetics | neurodevelopmental disorders | population genetics

Freely available online through the PNAS open access option.

Author contributions: X.Z., J.S., K.Y., and M.W. designed research; X.Z., K.Y., and M.W. performed research; X.Z., V.K., C. Lajonchere, D.H.G., K.L., P.L., S.Q., C. Lord, K.Y., and M.W. contributed new reagents/analytic tools; X.Z., A.L., D.H.G., S.Q., C. Lord, J.S., K.Y., and M.W. analyzed data; and X.Z., K.Y., and M.W. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705803104/DC1.

**To whom correspondence may be addressed. E-mail: kye{at}aecom.yu.edu or wigler{at}cshl.edu

© 2007 by The National Academy of Sciences of the USA


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