Detailed annotations of the identified variants.

BackgroundEpidermolysis 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 highlight the recurrent and novel genetic abnormalities that cause EB in the Western region of Saudi Arabia.MethodsTwelve Middle Eastern Arab families affected by Epidermolysis Bullosa (EB) were recruited from dermatology clinic from King Abdullah Medical Complex in Jeddah. Detailed clinical phenotyping was conducted for each patient to document EB-associated symptoms and to accurately determine the disease subtypes. Whole Exome Sequencing (WES) was performed to identify genetic variants associated with EB, and the resulting variants were classified by the guidelines of the American College of Medical Genetics and Genomics (ACMG). Additionally, multiple bioinformatics tools were employed to evaluate the pathogenicity of the detected variants. Variant segregation with disease phenotype was confirmed within the families using Sanger sequencing.ResultsWe identified 11 genetic variants, including three novel variants, in the COL7A1 (NM_000094.4), COL17A1 (NM_000494.4), and LAMB3 (NM_000228.3) genes across 12 EB families. The COL7A1 variants included frameshift variants (c.5924_5927del and c.6268_6269del), nonsense variants (c.1633C > T, c.1837C > T, c.2005C > T, and c.5888G > A), missense variants (c.4448G > A and c.8245G > A), and splice-site variants (c.6751-1G > A and c.8305-1G > A). Additionally, a splice-site variant was identified in COL17A1 (NM_000494.4; c.1394G > A) and another in LAMB3 (NM_000228.3; c.1977-1G > A). Bioinformatics analysis predicted these variants to be likely pathogenic because they disrupt collagen VII, XVII, and laminin 332, proteins essential for skin stability. Frameshift and nonsense variants introduce premature stop codons, leading to truncated or degraded transcripts. Splice-site variants likely cause aberrant splicing, disrupting the reading frame and impairing protein function.ConclusionWES is an effective first-line diagnostic tool for identifying EB-associated variants. This study reveals locus and allelic heterogeneity in EB cases from Saudi Arabia. The findings underscore the importance of early genetic screening for improving genetic counseling in high-consanguinity populations and emphasize the need for large-scale genetic studies in the country.