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Hum Mutat ; 41(12): 2087-2093, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32906221

RESUMO

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316-7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.


Assuntos
Síndrome de Ellis-Van Creveld/genética , Dedos/anormalidades , Predisposição Genética para Doença , Defeitos dos Septos Cardíacos/genética , Proteínas de Membrana/genética , Mutação/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Adulto , Animais , Criança , Pré-Escolar , Síndrome de Ellis-Van Creveld/diagnóstico por imagem , Família , Feminino , Dedos/diagnóstico por imagem , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Humanos , Masculino , Camundongos , Linhagem , Polidactilia/diagnóstico por imagem , Dedos do Pé/diagnóstico por imagem
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