Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.
Genet Med
; 21(5): 1121-1130, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30293986
ABSTRACT
PURPOSE:
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.METHODS:
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.RESULTS:
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.CONCLUSION:
Robust identification of CNVs by GS is possible within a clinical testing environment.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Raras
/
Variações do Número de Cópias de DNA
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Doenças não Diagnosticadas
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
/
Guideline
/
Incidence_studies
/
Observational_studies
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Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
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Adult
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Child
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Child, preschool
/
Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Genet Med
Ano de publicação:
2019
Tipo de documento:
Article