# Rare Mutations and Autism Spectrum Disorders

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $732,318

## Abstract

ABSTRACT
Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of
autism but most of the genetic architecture has not yet been understood. Most CNVs associated with autism
are large and the majority of pathogenic genes have not been proven. The goal of this proposal is to
significantly increase the yield of high-impact autism mutations by focusing on the discovery of understudied
classes of rare variants from whole-genome sequence data being generated from 35,000 samples from autism
families. This proposal focuses on rare, gene-disruptive mutations and leverages the additional sensitivity
afforded by whole-genome shotgun sequencing data, novel CNV discovery methods, and particular patterns of
gene-disruptive and missense mutation to increase yield of pathogenic mutations. Our target will include the
discovery and validation of smaller and more complex structural variants (including CNVs), clustered de novo
missense mutations, and private, gene-disruptive mutations transmitted preferentially from mothers to sons.
We will test these candidates by rapid targeted sequencing in 15,000 additional cases where patient recontact
and familial follow-up is possible. We propose to select 10 genes with the highest burden of mutation for further
clinical evaluation, phenotypic variability, and comprehensive genetic characterization. This proposal
specifically focuses on application of novel genomic methods, recurrent mutations, and inheritance patterns to
discover pathogenic variants in order to develop a more sophisticated model to explain the genetic architecture
of autism. As part of this effort, we will quantify and compare the risk of different classes of mutation for autism
and investigate transmission disequilibrium differences depending on the parent of origin and gender of
proband. The end product of this analysis will be the identification and characterization of new classes of highly
penetrant genic mutations that contribute significantly to etiology of autism, providing targets for clinical
diagnostics and future therapeutics.

## Key facts

- **NIH application ID:** 9867742
- **Project number:** 5R01MH101221-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Evan Eichler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $732,318
- **Award type:** 5
- **Project period:** 2013-08-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867742

## Citation

> US National Institutes of Health, RePORTER application 9867742, Rare Mutations and Autism Spectrum Disorders (5R01MH101221-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9867742. Licensed CC0.

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