Your browser doesn't support javascript.
loading
Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.
Lemire, Gabrielle; Sanchis-Juan, Alba; Russell, Kathryn; Baxter, Samantha; Chao, Katherine R; Singer-Berk, Moriel; Groopman, Emily; Wong, Isaac; England, Eleina; Goodrich, Julia; Pais, Lynn; Austin-Tse, Christina; DiTroia, Stephanie; O'Heir, Emily; Ganesh, Vijay S; Wojcik, Monica H; Evangelista, Emily; Snow, Hana; Osei-Owusu, Ikeoluwa; Fu, Jack; Singh, Mugdha; Mostovoy, Yulia; Huang, Steve; Garimella, Kiran; Kirkham, Samantha L; Neil, Jennifer E; Shao, Diane D; Walsh, Christopher A; Argilli, Emanuela; Le, Carolyn; Sherr, Elliott H; Gleeson, Joseph G; Shril, Shirlee; Schneider, Ronen; Hildebrandt, Friedhelm; Sankaran, Vijay G; Madden, Jill A; Genetti, Casie A; Beggs, Alan H; Agrawal, Pankaj B; Bujakowska, Kinga M; Place, Emily; Pierce, Eric A; Donkervoort, Sandra; Bönnemann, Carsten G; Gallacher, Lyndon; Stark, Zornitza; Tan, Tiong Yang; White, Susan M; Töpf, Ana.
Afiliación
  • Lemire G; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical S
  • Sanchis-Juan A; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospi
  • Russell K; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Baxter S; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chao KR; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Singer-Berk M; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Groopman E; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • Wong I; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • England E; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • Goodrich J; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Pais L; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Center for Genomi
  • Austin-Tse C; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • DiTroia S; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Center for Genomi
  • O'Heir E; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Center for Genomi
  • Ganesh VS; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical S
  • Wojcik MH; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical S
  • Evangelista E; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Snow H; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Osei-Owusu I; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Fu J; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospi
  • Singh M; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical S
  • Mostovoy Y; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Huang S; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Garimella K; Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kirkham SL; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • Neil JE; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
  • Shao DD; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Walsh CA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
  • Argilli E; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
  • Le C; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
  • Sherr EH; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
  • Gleeson JG; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Shril S; Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • Schneider R; Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • Hildebrandt F; Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • Sankaran VG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Madden JA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
  • Genetti CA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
  • Beggs AH; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Bost
  • Agrawal PB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Bost
  • Bujakowska KM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
  • Place E; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
  • Pierce EA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
  • Donkervoort S; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Bönnemann CG; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Gallacher L; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • Stark Z; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • Tan TY; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • White SM; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • Töpf A; John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Am J Hum Genet ; 111(5): 863-876, 2024 May 02.
Article en En | MEDLINE | ID: mdl-38565148
ABSTRACT
Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.
Asunto(s)
Palabras clave
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Raras / Variaciones en el Número de Copia de ADN / Exoma / Secuenciación del Exoma Límite: Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Raras / Variaciones en el Número de Copia de ADN / Exoma / Secuenciación del Exoma Límite: Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article