Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.

Autor: Riggs ER; Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA., Nelson T; Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA., Merz A; Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA., Ackley T; Michigan Medical Genetics Laboratories (MMGL), University of Michigan, Ann Arbor, MI, USA., Bunke B; EGL Genetics, Tucker, GA, USA., Collins CD; EGL Genetics, Tucker, GA, USA.; Perkin Elmer Genomics, Branford, CT, USA., Collinson MN; Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, Wiltshire, UK., Fan YS; University of Miami Miller School of Medicine, Miami, FL, USA., Goodenberger ML; Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Golden DM; Human Genetics Laboratory, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA., Haglund-Hazy L; Michigan Medical Genetics Laboratories (MMGL), University of Michigan, Ann Arbor, MI, USA., Krgovic D; University Medical Centre Maribor, Laboratory of Medical Genetics, Maribor, Slovenia.; Faculty of Medicine, University of Maribor, Maribor, Slovenia., Lamb AN; ARUP Laboratories, Salt Lake City, UT, USA.; University of Utah, Salt Lake City, UT, USA., Lewis Z; ARUP Laboratories, Salt Lake City, UT, USA., Li G; GeneDx, Gaithersburg, MD, USA., Liu Y; Clinical Cytogenomics Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA., Meck J; GeneDx, Gaithersburg, MD, USA., Neufeld-Kaiser W; Clinical Cytogenomics Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA., Runke CK; Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Sanmann JN; Human Genetics Laboratory, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA., Stavropoulos DJ; Genome Diagnostics, The Hospital for Sick Children, University of Toronto, Canada., Strong E; Genome Diagnostics, The Hospital for Sick Children, University of Toronto, Canada., Su M; University of Miami Miller School of Medicine, Miami, FL, USA., Tayeh MK; Michigan Medical Genetics Laboratories (MMGL), University of Michigan, Ann Arbor, MI, USA., Kokalj Vokac N; University Medical Centre Maribor, Laboratory of Medical Genetics, Maribor, Slovenia.; Faculty of Medicine, University of Maribor, Maribor, Slovenia., Thorland EC; Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Andersen E; ARUP Laboratories, Salt Lake City, UT, USA.; University of Utah, Salt Lake City, UT, USA., Martin CL; Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2018 Nov; Vol. 39 (11), pp. 1650-1659.
DOI: 10.1002/humu.23610
Abstrakt: Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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