Long-read genome sequencing identifies causal structural variation in a Mendelian disease.
Genet Med
; 20(1): 159-163, 2018 Jan.
Article
em En
| MEDLINE
| ID: mdl-28640241
ABSTRACT
PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
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Genoma Humano
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Análise de Sequência de DNA
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Predisposição Genética para Doença
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Genômica
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Estudos de Associação Genética
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Doenças Genéticas Inatas
Tipo de estudo:
Guideline
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Prognostic_studies
Limite:
Child
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article