Our unique resource of extended pedigrees with autism spectrum disorder (ASD) will allow us to make important contributions to genetic studies of ASD. We will sequence family members from the most informative pedigrees to study genetic variation contributing to ASD and related phenotypes. We will work to discover new variation, and also use the resource to characterize variants in conjunction with existing whole exome data available through our collaborations. We will test findings in up to 10 other families available from the Autism Genome Project (AGP) network of collaborators. We will also make the resource available to the broader scientific community. Extended families offer an excellent opportunity to identify and study genetic variation, giving a complementary approach to ongoing studies of simplex and small multiplex families. The current collection of families represents some of the largest pedigrees with ASD in the world. We have already detected significant linkage evidence in some of these families with clinical diagnosis and also with related phenotypes, including gender;Full Scale IQ;discrepancy between verbal and nonverbal IQ;language delay, Insistence on Sameness, Repetitive Sensory-Motor Actions (RSMA), overall clinical severity, and regressive onset (all derived from the ADI);head circumference;and the Broader Autism Phenotype. Sequence data in these extended families will result in highly accurate and extensive genetic information. We will identify familial variation in these data, and predict potentially deleterious variants using new informatics approaches. We will refine information about risk by comparing to ongoing sequence projects. We will also use the ongoing sequence projects to help prioritize the familial variant discovery, and choose the best for replication efforts in other AGP families. Finally, we will investigate sequence variants found by simplex/small family sequencing to determine specificity and penetrance in our extended families. Our proposed project will benefit from the continued collaboration of excellent molecular, analytic, and clinical expertise in the Autism Genome Project to enable the most effective use of this unique resource.

Public Health Relevance

Autism Spectrum Disorder (ASD) imposes an enormous psychological and economic burden on affected individuals, their families, and society. We will sequence family members in a unique resource of up to 40 of the world's largest extended ASD families to study genetic variation contributing to ASD. The planned studies are ideally timed to complement and enhance findings from ongoing sequence studies of ASD in cases and small families.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-PSE-H (60))
Program Officer
Senthil, Geetha
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Pinto, Dalila; Delaby, Elsa; Merico, Daniele et al. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94:677-94
Carayol, Jérôme; Schellenberg, Gerard D; Dombroski, Beth et al. (2014) A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism. Front Genet 5:33
Lin, Chiao-Feng; Valladares, Otto; Childress, D Micah et al. (2013) DRAW+SneakPeek: analysis workflow and quality metric management for DNA-seq experiments. Bioinformatics 29:2498-500