Exome sequencing identifies the first genetic determinants of sirenomelia in humans.
Hum Mutat
; 41(5): 926-933, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-32058622
ABSTRACT
Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Predisposição Genética para Doença
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Ectromelia
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Estudos de Associação Genética
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Sequenciamento do Exoma
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article