Marker Chromosome Genomic Structure and Temporal Origin Implicate a Chromoanasynthesis Event in a Family with Pleiotropic Psychiatric Phenotypes

Overview

Journal Hum Mutat

Specialty Genetics

Date 2018 Apr 27

PMID 29696747

Citations 17

Authors

Christopher M Grochowski

Shen Gu

Bo Yuan

Julia Tcw

Kristen J Brennand

Jonathan Sebat

Dheeraj Malhotra

Shane McCarthy

Uwe Rudolph

Anna Lindstrand

Zechen Chong

Deborah L Levy

James R Lupski

Claudia M B Carvalho

Affiliations

Soon will be listed here.

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 three duplications and three 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.

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