Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.

Adolescent Child Child, Preschool Chromosome Mapping / methods Cohort Studies DNA Copy Number Variations / genetics Female Genetic Testing / methods Genome, Human Genomics / methods Humans Infant Male Rare Diseases / diagnosis Undiagnosed Diseases / diagnosis Whole Genome Sequencing / methods Young Adult

copy number variation (CNV) microarray rare and undiagnosed disease structural variation (SV) whole genome sequencing (WGS)

Journal

Genetics in medicine : official journal of the American College of Medical Genetics

ISSN: 1530-0366

Titre abrégé: Genet Med

Pays: United States

ID NLM: 9815831

Informations de publication

Date de publication:
05 2019

Historique:

received: 14 02 2018

accepted: 28 08 2018

pubmed: 9 10 2018

medline: 14 2 2020

entrez: 9 10 2018

Statut: ppublish

Résumé

Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. Robust identification of CNVs by GS is possible within a clinical testing environment.

Identifiants

DOI: 10.1038/s41436-018-0295-y PMID: 30293986 PMC: PMC6752263

pubmed: 30293986

doi: 10.1038/s41436-018-0295-y

pii: S1098-3600(21)01471-4

pmc: PMC6752263

doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1121-1130

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