SFARI | Topic: Genetics

Integrated copy number variant analysis of SPARK exomes

Evan Eichler aims to significantly increase the yield of high-impact autism mutations by focusing on the discovery of both copy number and single nucleotide variants in approximately 15,000 individuals (4,500 families with autism) from SPARK. Using established and novel computational pipelines, his laboratory will work with the SPARK consortium to generate a high-confidence set of potential pathogenic variants and then integrate these data into larger genetic variant databases to pinpoint pathogenic variants and novel genes associated with autism.

MAP1B mutations cause intellectual disability and extensive white matter deficit.

Interactome perturbation screen to identity damaging de novo missense mutations in autism

Haiyuan Yu, Bernie Devlin and Kathryn Roeder aim to develop an experimentally and computationally integrated interactome perturbation screening pipeline and additional analytical methods to study the functional impact of de novo missense mutations in autism.

SSC-ASC Whole-Genome Sequencing Consortium (project 4): Functional analysis of mutations in untranslated regions

Joseph Dougherty will assess the functional consequences of mutations in untranslated regions (UTRs), furthering our understanding of the risk burden of noncoding variants in ASD. This project is part of a number of linked projects within the SSC-ASC Whole-Genome Sequencing Consortium.

Biallelic variants in VARS in a family with two siblings with intellectual disability and microcephaly: Case report and review of the literature.

Impact and mechanisms of paternal gonadal mosaicism on risk for autism

Joseph Gleeson proposes to measure gonadal mosaicism for the presence of ASD-causative mutations. He also plans to use this information to stratify males into those with baseline risk and those with high risk of fathering a child with ASD.

Gene regulatory control of prefrontal cortex development and evolution

Studying the development of the human midfetal prefrontal cortex (PFC) is integral to understanding the pathophysiology of ASD. Nenad Sestan aims to generate a multispecies comprehensive tissue-level and single-cell profile of the midfetal PFC to identify pertinent gene regulatory pathways and candidate genes. The function of identified ASD-relevant pathways will then be assessed in CRISPR-based targeted deletion/insertion mouse lines.

SSC-ASC Whole-Genome Sequencing Consortium (project 1): Association testing

The SSC-ASC Whole-Genome Sequencing Consortium has been established to discover de novo and inherited genomic variation that increase risk for ASD. In project one of four linked projects, Stephan Sanders will reprocess existing whole-genome sequencing data from thousands of ASD families using a common standardized pipeline to identify noncoding variants associated with ASD.

Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.

SSC-ASC Whole-Genome Sequencing Consortium (project 3): Discovery and functional characterization of structural variation in autism

Michael Talkowski will assess the mutational spectrum of structural variation associated with autism risk, as part of a linked number of projects within the SSC-ASC Whole-Genome Sequencing Consortium.