Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes
| Autor: | Muhammad Naeem, Sakina Rehman, Muhammad Erfan, Uzma Ali, Fehmida Farid Khan, Naima Khan, Amir Ejaz, Zubair M. Ahmed |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.disease_cause Biochemistry PLEC whole exome sequencing 030207 dermatology & venereal diseases 0302 clinical medicine Pakistan Exome sequencing ITGB4 Genetics Sanger sequencing Mutation integumentary system Homozygote Integrin beta4 Phenotype QR1-502 Neoplasm Proteins Pedigree EBS-Ogna symbols Female Epidermolysis bullosa Collagen Type VII Genetic counseling Biology Microbiology Article 03 medical and health sciences symbols.namesake Exome Sequencing medicine Humans Family epidermolysis bullosa Molecular Biology Gene Genetic diversity Genetic Variation Membrane Proteins medicine.disease 030104 developmental biology Plectin Laminin Cell Adhesion Molecules |
| Zdroj: | Biomolecules Biomolecules, Vol 11, Iss 620, p 620 (2021) Volume 11 Issue 5 |
| ISSN: | 2218-273X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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