Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation.

Am J Hum Genet
Authors
Keywords
Abstract

Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome. One remarkably common class of complex rearrangement, which we term dupINVdup, involves two closely located duplications ("paired duplications") that flank the breakpoints of an inversion. This complex variant class is cryptic to CMA, but we observed it in 8.1% of all subjects. We also detected other paired-duplication signatures and duplication-mediated complex rearrangements in 15.8% of all ASD subjects. Breakpoint analysis showed that the predominant mechanism of formation of these complex duplication-associated variants was microhomology-mediated repair. On the basis of the striking prevalence of dupINVdups in this cohort, we explored the landscape of all inversion variation among the 235 highest-quality libraries and found abundant complexity among these variants: only 39.3% of inversions were canonical, or simple, inversions without additional rearrangement. Collectively, these findings indicate that dupINVdups, as well as other complex duplication-associated rearrangements, represent relatively common sources of genomic variation that is cryptic to population-based microarray and low-depth whole-genome sequencing. They also suggest that paired-duplication signatures detected by CMA warrant further scrutiny in genetic diagnostic testing given that they might mark complex rearrangements of potential clinical relevance.

Year of Publication
2015
Journal
Am J Hum Genet
Volume
97
Issue
1
Pages
170-6
Date Published
2015 Jul 02
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2015.05.012
PubMed ID
26094575
PubMed Central ID
PMC4571023
Links
Grant list
T32 HD007396 / HD / NICHD NIH HHS / United States
R00 MH095867 / MH / NIMH NIH HHS / United States
R00MH095867 / MH / NIMH NIH HHS / United States
GM061354 / GM / NIGMS NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
HD007396 / HD / NICHD NIH HHS / United States