A family of Pakistani origin, segregating polydactyly, and phalangeal synostosis in an autosomal dominant manner, has been investigated and presented in the present report. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing, revealed a heterozygous missense variant [c.G1696A, p.(Gly566Ser)] in the LRP4 gene located on human chromosome 11p11.2. Homology protein modeling revealed the mutant Ser566 generated new interactions with at least four other amino acids and disrupted protein folding and function. Our findings demonstrated the first direct evidence of involvement of LRP4 in causing polydactyly and phalangeal synostosis in the same family. This study highlighted the importance of inclusion of LRP4 gene in screening individuals presenting polydactyly in hands and feet, and phalangeal synostosis in the same family.

中文翻译：

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巴基斯坦血统家族中 LDL 受体相关蛋白编码基因 LRP4 的变异导致多指和指骨骨联结

本报告对一个起源于巴基斯坦的家族进行了调查，该家族以常染色体显性方式分离多指和指骨骨联。全外显子组测序 (WES)，然后使用桑格测序进行分离分析，揭示了位于人类染色体 11p11.2 上的LRP4基因中的杂合错义变异 [c.G1696A, p.(Gly566Ser)]。同源蛋白质模型揭示了突变体 Ser566 与至少四种其他氨基酸产生了新的相互作用，并破坏了蛋白质折叠和功能。我们的研究结果首次证明了LRP4参与导致同一家族中的多指和指骨骨联结的直接证据。这项研究强调了纳入LRP4基因在筛查同一家族中手脚多指畸形和指骨骨融合的个体中的重要性。