Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes.

Fehmida F Khan,Sakina Rehman,Naima Khan,Muhammad Naeem,Zubair M Ahmed,Amir Ejaz,Muhammad Erfan,Uzma Ali

doi:10.3390/biom11050620

Abstract

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.

Highlights

Epidermolysis bullosa (EB) is a diverse group of rare genodermatoses characterized by moderate to severe fragility of epithelial tissues, with blistering and erosions of the skin [1,2]
There are four main types of EB based on the level of skin damage at the ultrastructural level, and more than 30 subtypes based on clinical outcomes, inheritance and molecular aberrations [9]
It is difficult to accurately diagnose the type and subtype of EB especially in newborns, which is vital for prognostics, genetic counseling and patient management [13]

Summary

Introduction

Epidermolysis bullosa (EB) is a diverse group of rare genodermatoses characterized by moderate to severe fragility of epithelial tissues, with blistering and erosions of the skin [1,2]. Skin fragility, blistering or erosion may be associated with some or all of the following: nail dystrophy, milia, crusts and scarring [3]. Signs typically appear at or near birth and persist over a lifetime. The onset of lesions in some individuals may not appear until adolescence or early adult life. Blistering may improve with increasing age in some variants [4,5]. Epidermolysis bullosa affects all ethnic groups without clear gender bias [6], with an estimated prevalence of about half a million people worldwide, many of whom are children [7]

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Conclusion