Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes.

TitleMarker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes.
Publication TypeJournal Article
Year of Publication2018
AuthorsGrochowski, CM, Gu, S, Yuan, B, Tcw, J, Brennand, KJ, Sebat, J, Malhotra, D, McCarthy, S, Rudolph, U, Lindstrand, A, Chong, Z, Levy, DL, Lupski, JR, Carvalho, CMB
JournalHum Mutat
Date Published2018 Apr 25
ISSN1098-1004
Abstract

Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed 3 duplications and 3 triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline-level event in the proband's maternal grandmother. Whole-genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life-cycle genesis, and propose a DNA replicative/repair mechanism underlying formation. This article is protected by copyright. All rights reserved.

DOI10.1002/humu.23537
Alternate JournalHum. Mutat.
PubMed ID29696747
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States