Journal article
Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk
Cold Spring Harbor molecular case studies, Vol.4(6), p.a003285
12/2018
DOI: 10.1101/mcs.a003285
PMCID: PMC6318775
PMID: 30559312
Abstract
Over the past decade, a focus on de novo mutations has rapidly accelerated gene discovery in autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental disorders (NDDs). However, recent studies suggest that only a minority of cases are attributable to de novo mutations, and instead these disorders often result from an accumulation of various forms of genetic risk. Consequently, we adopted an inclusive approach to investigate the genetic risk contributing to a case of male monozygotic twins with ASD and ID. At the time of the study, the probands were 7 yr old and largely nonverbal. Medical records indicated a history of motor delays, sleep difficulties, and significant cognitive deficits. Through whole-genome sequencing of the probands and their parents, we uncovered elevated common polygenic risk, a coding de novo point mutation in
, an ultra-rare homozygous regulatory variant in
, inherited rare variants in
, and a maternally inherited X-linked deletion situated in a noncoding regulatory region between
and
Although each of these genes has been directly or indirectly associated with NDDs, evidence suggests that no single variant adequately explains the probands' phenotype. Instead, we propose that the probands' condition is due to the confluence of multiple rare variants in the context of a high-risk genetic background. This case emphasizes the multifactorial nature of genetic risk underlying most instances of NDDs and aligns with the "female protective model" of ASD.
Details
- Title: Subtitle
- Whole-genome sequencing in a family with twin boys with autism and intellectual disability suggests multimodal polygenic risk
- Creators
- Brooke McKenna - Department of Psychology, Emory University, Atlanta, Georgia 30322, USATanner Koomar - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USAKevin Vervier - Host-Microbiota Interactions Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United KingdomJamie Kremsreiter - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USAJacob J Michaelson - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cold Spring Harbor molecular case studies, Vol.4(6), p.a003285
- DOI
- 10.1101/mcs.a003285
- PMID
- 30559312
- PMCID
- PMC6318775
- NLM abbreviation
- Cold Spring Harb Mol Case Stud
- ISSN
- 2373-2865
- eISSN
- 2373-2873
- Publisher
- United States
- Grant note
- R01 DC014489 / NIDCD NIH HHS R01 MH105527 / NIMH NIH HHS
- Language
- English
- Date published
- 12/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984070976002771
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