A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype-Phenotype Correlations.
A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype-Phenotype Correlations.
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HOXD13 的一种新型错义变异体通过损害下游基因表达引起非典型多指畸形以及基因型-表型相关性的文献综述
DOI：
10.3389/fgene.2021.731278
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发表时间：
2021
影响因子：
3.7
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Guo R;Fang X;Mao H;Sun B;Zhou J;An Y;Wang B
并指（SPD）是一种遗传性先天性肢体畸形，具有不同的并指（SPD），命名为SPD 1，SPD 2和SPD 3。SPD 1是由HOXD 13突变引起的，HOXD 13是一种对肢体发育至关重要的同源框转录因子。据报道，超过143名SPD患者携带HOXD 13突变，但缺乏基因型-表型相关性。我们报告了一个新的错义突变的c。925 A> T（p.I309F）突变，并在12个中国SPD家系中通过全外显子组测序（WES）鉴定出HOXD 13基因的3个不同丙氨酸插入突变。与分子模拟和免疫荧光显示的多聚丙氨酸延伸倾向于形成α-螺旋并导致蛋白质在细胞质中聚集不同，c。925 A> T突变损害EPHA 7的下游转录。我们收集了文献结果，并分析了53个家庭的173个SPD个体的基因型-表型特征，其中包括12个新发现的家庭。在HOXD 13相关个体中，突变分布在三个区域：多聚丙氨酸、同源框和非同源框。多聚丙氨酸延伸是最常见的变异（45%），其次是错义突变（32%），主要是在同源异型盒中，而功能丧失（LOF）变异更可能在非同源异型盒中。此外，更严重的程度和经典的SPD与多聚丙氨酸突变相关，尽管错义变体与手和脚的短指和并指相关，LOF变体与手的单指相关。我们的研究拓宽了HOXD 13突变谱，揭示了三种不同变体的特征及其SPD的严重程度，与HOXD 13突变位点相关的基因型-表型相关性提供了临床见解，包括遗传咨询。
Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.
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HOXD13 同源域突变导致两个中国家族 1-c 型并指
影响因子：
3.7
作者：
Dai L;Liu D;Song M;Xu X;Xiong G;Yang K;Zhang K;Meng H;Guo H;Bai Y
通讯作者：
Bai Y
影响因子：
64.5
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Hnisz, Denes
影响因子：
64.5
作者：
KISSINGER, CR;LIU, BS;PABO, CO
通讯作者：
PABO, CO
影响因子：
3.5
作者：
Brown, LY;Odent, S;Muenke, M
通讯作者：
Muenke, M
影响因子：
3.5
作者：
Fantini, Sebastian;Vaccari, Giulia;Zappavigna, Vincenzo
通讯作者：
Zappavigna, Vincenzo