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Am J Hum Genet. 2014 Oct 2;95(4):454-61. doi: 10.1016/j.ajhg.2014.09.005.

Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders.

Author information

1
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
2
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
3
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
4
Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
5
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
6
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA.
7
Departments of Computational Medicine & Bioinformatics and Human Genetics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
8
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
9
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
10
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
11
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
12
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: talkowski@chgr.mgh.harvard.edu.
13
Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: doylea@helix.mgh.harvard.edu.

Abstract

Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping. Here, we performed whole-genome sequencing using large-insert jumping libraries to delineate both cytogenetically visible and cryptic SVs in a single test among 30 clinically referred youth representing a range of severe neuropsychiatric conditions. We detected 96 SVs per person on average that passed filtering criteria above our highest-confidence resolution (6,305 bp) and an additional 111 SVs per genome below this resolution. These SVs rearranged 3.8 Mb of genomic sequence and resulted in 42 putative loss-of-function (LoF) or gain-of-function mutations per person. We estimate that 80% of the LoF variants were cryptic to clinical CMA. We found myriad complex and cryptic rearrangements, including a "paired" duplication (360 kb, 169 kb) that flanks a 5.25 Mb inversion that appears in 7 additional cases from clinical CNV data among 47,562 individuals. Following convergent genomic profiling of these independent clinical CNV data, we interpreted three SVs to be of potential clinical significance. These data indicate that sequence-based delineation of the full SV mutational spectrum warrants exploration in youth referred for neuropsychiatric evaluation and clinical diagnostic SV screening more broadly.

PMID:
25279985
PMCID:
PMC4185111
DOI:
10.1016/j.ajhg.2014.09.005
[Indexed for MEDLINE]
Free PMC Article

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