RESUMO
Aims: Split-hand/split-foot malformation (SHFM) is a developmental and congenital limb malformation characterized by variable degrees of medial clefting or absence of one or more digits in hands and/or feet. The aim of this study was to identify the underlying cause of three consanguineous Pakistani families showing various types of SHFM-related features. Materials and Methods: Standard molecular methods, including whole-genome sequencing (WGS), whole-exome sequencing (WES), microsatellite markers-based genotyping, and Sanger sequencing were performed to search for the likely causative variants. Results: In family A, WES revealed a novel homozygous missense variant [c.338G>A, p.(Gly113Asp)] in the WNT10B gene. In family B, microsatellite-based genotyping followed by Sanger sequencing revealed a novel homozygous 13 base pairs deletion [c.884-896delTCCAGCCCCGTCT, p.(Phe295Cysfs*87)] in the same gene. In family C, WGS divulged a previously reported heterozygous missense variant [c.956G>A, p.(Arg319His)] in the TP63 gene. Conclusions: Mapping and sequencing genes and variants for severe skeletal disorders, such as SHRM, will facilitate establishing specific genotype-phenotype correlations and providing genetic counseling for the families suffering from such conditions.
Assuntos
Deformidades Congênitas dos Membros/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto , Criança , Pré-Escolar , Família , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Deformidades Congênitas dos Membros/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Paquistão/epidemiologia , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequenciamento do Exoma , Proteínas Wnt/metabolismo , Adulto JovemRESUMO
Polydactyly is one of the most common congenital abnormal phenotype of autopod, which is characterized by extra supernumerary digit in hands/feet with or without well-developed bony structure within the digits. Preaxial polydactyly (PPD), postaxial polydactyly (PAP), and meso-axial (central) polydactyly are three different isoforms of polydactyly. Genetically, at least 10 genes have been identified causing nonsyndromic polydactyly. In the present study, we have investigated a large family segregating autosomal dominant form of nonsyndromic polydactyly. Whole exome sequencing followed by Sanger sequencing revealed a novel heterozygous missense variant (NM_005269.3; c.1064C>A; p.(Thr355Asn) in the gene GLI1 segregating with the disease phenotype within the family. This study presents first familial case of autosomal dominant form of polydactyly caused by the GLI1 variant.