Abstract：
Polydactyly is a human inherited disorder caused by to anomalies in the genes involved in autopod development. The disorder segregates in both autosomal recessive and autosomal dominant form. Up till now, eleven genes causing non-syndromic polydactyly, have been identified. This includes ZNF141, GLI3, ZRS in LMBR1, MIPOL1, PITX1, IQCE, GLI1, FMA92A1, KIAA0825, STKLD1, and DACH1. In the present study, we have investigated a large consanguineous family of Pakistani origin segregating polydactyly in autosomal recessive pattern. Clinical examination of affected individuals revealed a non-syndromic form of the disorder. Genetic study based on homozygosity mapping and Sanger sequencing using DNA of the normal and affected individuals found a novel homozygous missense sequence variant [NM_005269.3: c.1133C > T, p.(Ser378Leu)] in the GLI1 located on human chromosome 12q13.3. In silico analysis of the identified variant showed a significant change in the secondary structure of the mutant protein that affects its function. Findings of the present study expand the mutation spectrum of the GLI1. In addition, the study will help in prevention of the disorder through carrier testing and bringing awareness among families affected with polydactyly.
摘要：
多指是一种人类遗传性疾病，由涉及自足动物发育的基因异常引起。该疾病以常染色体隐性和常染色体显性形式分离。直到现在,11个基因导致非综合征多指畸形，已被确认。这包括ZNF141，GLI3，LMBR1中的ZRS，MIPOL1，PITX1，IQCE，GLI1、FMA92A1、KIAA0825、STKLD1和DACH1。在本研究中,我们调查了一个巴基斯坦血统的近亲大家族，以常染色体隐性遗传模式分离多指。受影响个体的临床检查显示该疾病的非综合征形式。基于纯合性作图和使用正常和受影响个体的DNA进行Sanger测序的遗传研究发现了一种新的纯合错义序列变体[NM_005269.3:c.113C>T，p。（Ser378Leu）]在位于人类染色体12q13.3上的GLI1中。鉴定的变体的计算机模拟分析表明，突变蛋白的二级结构发生了显着变化，从而影响了其功能。本研究的发现扩展了GLI1的突变谱。此外,这项研究将有助于通过携带者测试来预防这种疾病，并提高受多指影响的家庭的意识。
