Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.

Cell
Authors
Keywords
Abstract

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Year of Publication
2012
Journal
Cell
Volume
149
Issue
3
Pages
525-37
Date Published
2012 Apr 27
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2012.03.028
PubMed ID
22521361
PubMed Central ID
PMC3340505
Links
Grant list
HD065286 / HD / NICHD NIH HHS / United States
MH087123 / MH / NIMH NIH HHS / United States
GM061354 / GM / NIGMS NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
Intramural NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
R21 HD065286 / HD / NICHD NIH HHS / United States
F32 MH087123 / MH / NIMH NIH HHS / United States