Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes.
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.
['Khan|Fehmida F|FF|', 'Khan|Naima|N|', 'Rehman|Sakina|S|0000-0003-2253-0750', 'Ejaz|Amir|A|', 'Ali|Uzma|U|', 'Erfan|Muhammad|M|', 'Ahmed|Zubair M|ZM|0000-0003-2914-4502', 'Naeem|Muhammad|M|0000-0002-3894-3085']
D015815:Cell Adhesion Molecules D024143:Collagen Type VII D004820:Epidermolysis Bullosa D005190:Family D005260:Female D014644:Genetic Variation D006720:Homozygote D006801:Humans D039663:Integrin beta4 D007797:Laminin D008297:Male D008565:Membrane Proteins D009154:Mutation D009363:Neoplasm Proteins D010154:Pakistan D010375:Pedigree D010641:Phenotype D051190:Plectin D000073359:Whole Exome Sequencing
epidermolysis bullosa whole exome sequencing ITGB4 PLEC EBS-Ogna