GLI3 variants causing isolated polysyndactyly are not restricted to the protein's C-terminal third,Clinical Genetics

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GLI3 variants causing isolated polysyndactyly are not restricted to the protein's C-terminal third
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-09-05 , DOI: 10.1111/cge.14059
Henrike Lisa Sczakiel _{1,

2} , Wiebke Hülsemann ₃ , Manuel Holtgrewe ₄ , Angela Teresa Abad-Perez ₁ , Jonas Elsner ₁ , Sarina Schwartzmann ₁ , Denise Horn ₁ , Malte Spielmann _{2,

5,

6} , Stefan Mundlos _{1,

2} , Martin Atta Mensah _{1,

7}

Affiliation

Loss of function variants of GLI3 are associated with a variety of forms of polysyndactyly: Pallister-Hall syndrome (PHS), Greig-Cephalopolysyndactyly syndrome (GCPS), and isolated polysyndactyly (IPD). Variants affecting the N-terminal and C-terminal thirds of the GLI3 protein have been associated with GCPS, those within the central third with PHS. Cases of IPD have been attributed to variants affecting the C-terminal third of the GLI3 protein. In this study, we further investigate these genotype–phenotype correlations. Sequencing of GLI3 was performed in patients with clinical findings suggestive of a GLI3-associated syndrome. Additionally, we searched the literature for reported cases of either manifestation with mutations in the GLI3 gene. Here, we report 48 novel cases from 16 families with polysyndactyly in whom we found causative variants in GLI3 and a review on 314 previously reported GLI3 variants. No differences in location of variants causing either GCPS or IPD were found. Review of published data confirmed the association of PHS and variants affecting the GLI3 protein's central third. We conclude that the observed manifestations of GLI3 variants as GCPS or IPD display different phenotypic severities of the same disorder and propose a binary division of GLI3-associated disorders in either PHS or GCPS/polysyndactyly.

中文翻译：

导致分离的多指畸形的 GLI3 变体不限于蛋白质的 C 端第三个

GLI3的功能缺失变异与多种形式的多指畸形相关：Pallister-Hall 综合征 (PHS)、Greig-Cephalopolysyndactyly 综合征 (GCPS) 和孤立性多指畸形 (IPD)。影响 GLI3 蛋白 N 端和 C 端三分之一的变异与 GCPS 相关，中心三分之一与 PHS 相关。IPD 病例归因于影响 GLI3 蛋白 C 末端三分之一的变异。在这项研究中，我们进一步研究了这些基因型-表型相关性。在临床发现提示GLI3相关综合征的患者中进行GLI3测序。此外，我们在文献中搜索了GLI3突变的任何一种表现的报道病例基因。在这里，我们报告了来自 16 个多指畸形家族的 48 例新病例，我们在这些病例中发现了 GLI3 的致病变异，并对314 种先前报道的GLI3变异进行了回顾。没有发现导致 GCPS 或 IPD 的变异的位置差异。对已发表数据的审查证实了 PHS 和影响 GLI3 蛋白中央三分之一的变体的关联。我们得出结论，作为 GCPS 或 IPD 观察到的GLI3变体表现显示相同疾病的不同表型严重性，并提出 PHS 或 GCPS/多指畸形中 GLI3 相关疾病的二元划分。

更新日期：2021-11-03

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