Novel and Recurrent Epidermolysis Bullosa-Causing Variants in Families from Saudi Arabia

Abstract

Background: Epidermolysis Bullosa (EB) is a rare genetic disorder that results in fragile skin and blistering and may lead to mucous membrane involvement. The disease manifests in several subtypes, among which the most serious conditions are dystrophic and junctional EB. This study intends to shed some light on recurrent as well as novel genetic abnormalities that cause EB in the Western region of Saudi Arabia. 

Methods:  Twelve EB families in Saudi Arabia were recruited from clinical settings. Comprehensive clinical phenotyping was conducted in these patients to document the symptoms related to EB and classify disease subtypes precisely. Whole Exome Sequencing (WES) was used to identify EB-causing variants, which were classified as per the American College of Medical Genetics and Genomics (ACMG) guidelines. Additionally, different bioinformatics tools were used to evaluate their pathogenicity. Sanger sequencing validated the segregation of variants with disease in the affected families. 

Results: We identified 11 pathogenic variants, including 3 novels in COL7A1, COL17A1, and LAMB3 genes across the 12 EB families. The COL7A1 variants included frameshift (c.5924_5927del and c.6268_6269del,), nonsense (c.1633C>T, c.1837C>T, c.2005C>T, and c.5888G>A), missense (c.4448G>A, and c.8245G>A), and splice site (c.6751-1G>A). Additionally, splice site variants were detected in the COL17A1 () and LAMB3 genes (c.8305-1G>A and c.1977-1G>A, respectively). Bioinformatics analysis predicted These variants to be highly pathogenic because they disrupt collagen VII, XVII and laminin 332, which are essential for skin stability. Protein deficiency occurs due to frameshift and truncating mutations, and splice site changes impairing RNA processing. 

Conclusion: WES was an effective first-line diagnostic tool for identifying EB-associated variants. This study shows locus and allelic heterogeneity in the variants underlying EB in Saudi Arabia. The results highlight the role of genetic profiling in developing better genetic counselling for EB in high-consanguinity populations and highlight the need for large-scale genetic studies in the country.

Funding: This publication is based on work supported by The Saudi Society for Laboratory Medicine for funding the research.

Declaration of Interest: The authors declare that they have no conflict of interest.

Ethical Approval: This study was approved by the Biomedical Ethics and Research Committee at Al Borg Diagnostics, Jeddah, Saudi Arabia (Reference number: N06/24). Informed consent was obtained from each tested individual before genetic testing.

Keywords: Epidermolysis Bullosa, Genetic Testing, Saudi Arabia, Noval, Computational Biology.