# Rare Mutations and Autism Spectrum Disorders

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $704,178

## Abstract

ABSTRACT
Sporadic loss-of-function mutations, recurrent missense mutations, and copy number variants (CNVs) contribute
significantly to the etiology of autism, but much of the genetic architecture has not yet been understood. Most
known pathogenic CNVs are large and the significance of many of these gene mutations is still not known. 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 (n = 35,000 samples) and whole-exome
(n = 150,000 samples) sequence data being generated from autism families. This proposal focuses on ultra-
rare, gene-disruptive mutations and leverages the additional sensitivity afforded by whole-genome shotgun
sequencing data, novel CNV discovery methods, and transmission of ultra-rare inherited mutations to increase
yield of pathogenic mutations. Our target will include the discovery and validation of smaller and more complex
structural variants (including CNVs) and private gene-disruptive mutations not enriched in de novo mutation but
preferentially transmitted to autism children. We will assess the utility of high-fidelity long-read sequencing to
discover more complex forms of structural variation that have been missed by standard short-read sequencing
by investigating 100 unsolved cases with a higher likelihood of genetic risk. In addition, we propose to select 10
genes with evidence of de novo mutation for further clinical evaluation, phenotypic variability, and comprehensive
genetic characterization. This will include five genes where only de novo mutations have been observed
compared to five genes where both de novo and inherited mutations have been documented in order to
understand carrier phenotypes. This proposal specifically focuses on the 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. 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:** 10118951
- **Project number:** 2R01MH101221-09
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Evan Eichler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $704,178
- **Award type:** 2
- **Project period:** 2013-08-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118951

## Citation

> US National Institutes of Health, RePORTER application 10118951, Rare Mutations and Autism Spectrum Disorders (2R01MH101221-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10118951. Licensed CC0.

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