title: Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders.
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.
authors.affiliation: 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.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Collins
authors.affiliation: 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.
authors.forename: Stacey
authors.initials: S
authors.lastname: Eggert
authors.affiliation: Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Dushlaine
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Braaten
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stone
authors.affiliation: Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Chambert
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Doty
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Hillary
authors.initials: H
authors.lastname: Ditmars
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Blais
authors.affiliation: Departments of Computational Medicine & Bioinformatics and Human Genetics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Mills
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: McCarroll
authors.affiliation: 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.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: 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.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: 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.
authors.forename: Alysa E
authors.initials: AE
authors.lastname: Doyle
mesh_terms: D017668:Age of Onset; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D001523:Mental Disorders / Q000453:epidemiology / Q000235:genetics*; D046228:Microarray Analysis; D019636:Neurodegenerative Diseases / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D014481:United States / Q000453:epidemiology