title: Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation.
abstract: Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome. One remarkably common class of complex rearrangement, which we term dupINVdup, involves two closely located duplications ("paired duplications") that flank the breakpoints of an inversion. This complex variant class is cryptic to CMA, but we observed it in 8.1% of all subjects. We also detected other paired-duplication signatures and duplication-mediated complex rearrangements in 15.8% of all ASD subjects. Breakpoint analysis showed that the predominant mechanism of formation of these complex duplication-associated variants was microhomology-mediated repair. On the basis of the striking prevalence of dupINVdups in this cohort, we explored the landscape of all inversion variation among the 235 highest-quality libraries and found abundant complexity among these variants: only 39.3% of inversions were canonical, or simple, inversions without additional rearrangement. Collectively, these findings indicate that dupINVdups, as well as other complex duplication-associated rearrangements, represent relatively common sources of genomic variation that is cryptic to population-based microarray and low-depth whole-genome sequencing. They also suggest that paired-duplication signatures detected by CMA warrant further scrutiny in genetic diagnostic testing given that they might mark complex rearrangements of potential clinical relevance.
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics 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: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics 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: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics 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: Program in Medical and Population Genetics and Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors.forename: Fontina
authors.initials: F
authors.lastname: Kelley
authors.affiliation: Program in Medical and Population Genetics and Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mason
authors.affiliation: Program in Medical and Population Genetics and Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Margolin
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Eggert
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Elyse
authors.initials: E
authors.lastname: Mitchell
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jennelle C
authors.initials: JC
authors.lastname: Hodge
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94103, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA. Electronic address: talkowski@chgr.mgh.harvard.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D007446:Chromosome Inversion / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D015723:Gene Library; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D056916:Segmental Duplications, Genomic / Q000235:genetics*
chemical_list: D005819:Genetic Markers