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Hum Mutat. 2018 Jul;39(7):939-946. doi: 10.1002/humu.23537. Epub 2018 May 11.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
2
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
3
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York.
4
Beyster Center for Psychiatric Genomics, Department of Psychiatry, University of California at San Diego, San Diego, California.
5
Hoffmann-La Roche Ltd, Basel, Switzerland.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
7
Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts.
8
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
9
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
10
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
11
Department of Genetics and the Informatics Institute, The University of Alabama at Birmingham, Birmingham, Alabama.
12
Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts.
13
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
14
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
15
Texas Children's Hospital, Houston, Texas.

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.

KEYWORDS:

SNP analysis; chromosomal abnormalities; marker chromosome; microarrays; psychiatric genetics; structural variation

PMID:
29696747
PMCID:
PMC5995661
[Available on 2019-07-01]
DOI:
10.1002/humu.23537

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