PDF(Pubmed)
Abstract：
BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly.
METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.
RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species.
CONCLUSIONS: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.
METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.
RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species.
CONCLUSIONS: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.
摘要：
背景：多指，尤其是食指，仍然是一个有趣的异常，没有特定的基因或基因座与该表型明确相关。在这项研究中,我们对一个显示食指多指的三代家庭进行了调查。
方法：对患者进行外显子组测序，通过过滤来识别潜在的因果变异。通过Sanger测序对获得的变体进行验证，包括所有家庭成员。
结果：外显子组分析在先证者和所有受影响的家族成员中的GLI3蛋白的锌指DNA结合域发现了一个新的杂合错义变体（c.1482A>T;p.Gln494His）。值得注意的是,该变异体在谱系内未受影响的个体中不存在，强调其与多指表型的关联。计算分析表明，GLI3p.Gln494His会影响跨物种高度保守的残基。
结论：GLI3锌指DNA结合区是Sonichedgehog信号通路的重要组成部分，通过调节靶基因表达来协调胚胎发育的关键方面。这项新发现不仅为胚胎发育过程中控制多指的分子途径提供了有价值的见解，而且还具有在临床环境中增强这种疾病的诊断和筛查能力的潜力。
方法：对患者进行外显子组测序，通过过滤来识别潜在的因果变异。通过Sanger测序对获得的变体进行验证，包括所有家庭成员。
结果：外显子组分析在先证者和所有受影响的家族成员中的GLI3蛋白的锌指DNA结合域发现了一个新的杂合错义变体（c.1482A>T;p.Gln494His）。值得注意的是,该变异体在谱系内未受影响的个体中不存在，强调其与多指表型的关联。计算分析表明，GLI3p.Gln494His会影响跨物种高度保守的残基。
结论：GLI3锌指DNA结合区是Sonichedgehog信号通路的重要组成部分，通过调节靶基因表达来协调胚胎发育的关键方面。这项新发现不仅为胚胎发育过程中控制多指的分子途径提供了有价值的见解，而且还具有在临床环境中增强这种疾病的诊断和筛查能力的潜力。
