1. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder
- Author
-
Nicholas M. DiLullo, Nicholas Carriero, Bernie Devlin, Adam Yongxin Ye, Stephen Sanders, Vanessa H. Bal, Shan Dong, Michael F. Walker, Liping Wei, Stephanie Frahm, John F. Keaney, Jeanselle Dea, Kathryn Roeder, Nicole A. Teran, A. Jeremy Willsey, Michael Sheldon, Rehab O. Khalil, Sinem M. Sertel, Abha R. Gupta, Jake Gockley, Zafer Yüksel, Jeffrey D. Mandell, Catherine A.W. Sullivan, Zainulabedin Waqar, Luis E. Gonzalez, A. Gulhan Ercan-Sencicek, Matthew W. State, Michael DiCola, Andrew Brooks, John D. Overton, and Shrikant Mane
- Subjects
Proband ,Male ,Mutation rate ,frameshift mutation ,genetic association ,Medical Physiology ,genetic identification ,paternalism ,animal cell ,genetic risk ,open reading frame ,Fragile X Mental Retardation Protein ,single nucleotide polymorphism ,synapse ,genetic variability ,2.1 Biological and endogenous factors ,Aetiology ,indel mutation ,Child ,Frameshift Mutation ,lcsh:QH301-705.5 ,PHF3 gene ,Sequence Deletion ,Genetics ,Pediatric ,chromatin structure ,food and beverages ,regulating synaptic exocytosis 1 ,Phenotype ,unclassified drug ,Pedigree ,DNA-Binding Proteins ,Mental Health ,female ,Autism spectrum disorder ,protein protein interaction ,fragile X mental retardation protein ,sequence alignment ,KMT2E gene ,Female ,gene insertion ,parental age ,RIMS1 gene ,Child Development Disorders ,Intellectual and Developmental Disabilities (IDD) ,sex difference ,CHD2 gene ,autism ,Nerve Tissue Proteins ,mixed lineage leukemia protein 5 ,gene sequence ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Frameshift mutation ,animal tissue ,Sex Factors ,male ,GTP-Binding Proteins ,mental disorders ,medicine ,Humans ,controlled study ,human ,cell protein ,Indel ,gene ,Gene ,mouse ,Pervasive ,nonhuman ,gene deletion ,human cell ,intellectual impairment ,missense mutation ,Human Genome ,Chromosome ,DNA ,medicine.disease ,major clinical study ,human tissue ,Brain Disorders ,lcsh:Biology (General) ,Child Development Disorders, Pervasive ,mixed lineage leukemia protein ,Biochemistry and Cell Biology ,exome - Abstract
Summary: Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0–2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10−9), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. : Insertions and deletions (indels) have proven especially difficult to detect in exome sequencing data. Dong et al. now identify indels in exome data for 787 autism spectrum disorder (ASD) families. They demonstrate association between de novo indels that alter the reading frame and ASD. Furthermore, by observing clustering of indels in unrelated probands, they uncover two additional ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
- Published
- 2014
- Full Text
- View/download PDF