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Abstract：
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.
摘要：
目的：手裂/足裂畸形（SHFM）是一种发育和先天性肢体畸形，其特征是不同程度的内侧裂开或手部和/或足部缺少一个或多个手指。这项研究的目的是确定三个近亲巴基斯坦家庭表现出各种类型的SHFM相关特征的根本原因。材料和方法：标准分子方法，包括全基因组测序（WGS），全外显子组测序（WES），基于微卫星标记的基因分型，进行Sanger测序以寻找可能的致病变异。结果:在家庭A中,WES揭示了一个新的纯合错义变体[c.338G>A，p.(Gly113Asp)]在WNT10B基因中。在家庭B,基于微卫星的基因分型，然后进行Sanger测序，发现了一个新的纯合13个碱基对缺失[c.884-896delTCCAGCCCCCCGTCT，p.(Phe295Cysfs*87)]在同一基因中。在C家族,WGS泄露了先前报道的杂合错义变体[c.956G>A，p.(Arg319His)]在TP63基因中。结论：对严重骨骼疾病的基因和变异进行定位和测序，如SHRM,将有助于建立特定的基因型-表型相关性，并为患有此类疾病的家庭提供遗传咨询。
