Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes.
Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes.
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DOI：
10.3390/biom11050620
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发表时间：
2021-04-22
期刊：
影响因子：
5.5
通讯作者：
Naeem M
中科院分区：
文献类型：
--
作者：
Khan FF;Khan N;Rehman S;Ejaz A;Ali U;Erfan M;Ahmed ZM;Naeem M
大疱性表皮松解症(EB)包括一组罕见的斑点皮肤病，导致皮肤和粘膜起泡和侵蚀。在遗传学上，大约20个基因的致病变异已知会改变表皮内粘连和真皮-表皮锚定的结构和功能完整性，导致四种不同类型的EB。在这里，我们报告了从巴基斯坦不同地区招募的七个大家族中EB表型分离的潜在遗传原因。通过Sanger测序对候选变异进行分离分析，确定了8个致病变异，其中包括3个新变种(ITGB4：c.1285G>；T和c.3373G>；A；plc：c.1828A>；G)和5个以前报道的变种(COL7A1：c.6209G>；A和c.1573C>；T；FERMT1：c.676insC；LAMA3：c.151insG；LAMB3：c.1705C>；T)。所有已确定的变异在对照数据库中要么缺失，要么出现频率很低。我们的电子分析和三维(3D)分子建模支持这些变异对编码蛋白质的有害影响。有趣的是，我们报告了第一例与Plec基因纯合子变异相关的罕见EBS-OgnA隐性遗传形式。我们的研究突出了巴基斯坦人群EB的临床和遗传多样性，并扩大了EB的突变谱；它也可能对受影响家庭的产前诊断和遗传咨询有用。
Epidermolysis bullosa (EB) includes a group of rare gesnodermatoses that result in blistering and erosions of the skin and mucous membranes. Genetically, pathogenic variants in around 20 genes are known to alter the structural and functional integrity of intraepidermal adhesion and dermo-epidermal anchorage, leading to four different types of EB. Here we report the underlying genetic causes of EB phenotypes segregating in seven large consanguineous families, recruited from different regions of Pakistan. Whole exome sequencing, followed by segregation analysis of candidate variants through Sanger sequencing, identified eight pathogenic variants, including three novel (ITGB4: c.1285G>T, and c.3373G>A; PLEC: c.1828A>G) and five previously reported variants (COL7A1: c.6209G>A, and c.1573C>T; FERMT1: c.676insC; LAMA3: c.151insG; LAMB3: c.1705C>T). All identified variants were either absent or had very low frequencies in the control databases. Our in-silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Intriguingly, we report the first case of a recessively inherited form of rare EBS-Ogna associated with a homozygous variant in the PLEC gene. Our study highlights the clinical and genetic diversity of EB in the Pakistani population and expands the mutation spectrum of EB; it could also be useful for prenatal diagnosis and genetic counseling of the affected families.
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