Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous Marriages

Abstract

Dystrophic epidermolysis bullosa is a heritable skin disease manifesting with sub-lamina densa blistering, erosions, and chronic ulcers. COL7A1, encoding type VII collagen, has been identified as the candidate gene for dystrophic epidermolysis bullosa. In this study, we have identified COL7A1 mutations in a large multi-ethnic cohort of 152 extended Iranian families with high degree of consanguinity. The patients were diagnosed by clinical manifestations, histopathology, and immunoepitope mapping. Mutation detection consisted of a combination of single nucleotide polymorphism-based whole-genome homozygosity mapping, Sanger sequencing, and gene-targeted next-generation sequencing. A total of 104 distinct mutations in COL7A1 were identified in 149 of 152 families (98%), 56 (53%) of them being previously unreported. Ninety percent of these mutations were homozygous recessive, reflecting consanguinity in these families. Three recurrent mutations were identified in five or more families, and haplotype analysis suggested a founder effect in two of them. In conclusion, COL7A1 harbored mutations in the overwhelming majority of patients with dystrophic epidermolysis bullosa, and most of them in this Iranian cohort were consistent with autosomal recessive inheritance. The mutation profile attests to the impact of consanguinity in these families.

Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1 ) in a patient with concomitant simplex and junctional epidermolysis bullosa

“…The phenotypic heterogeneity of different forms of EB reflects the fact that as many as 20 different genes encoding the components of the dermal–epidermal attachment complexes harbor mutations in different subtypes of EB (Uitto et al, ). Recently, a number of NGS approaches have been adopted, including gene‐targeted panels, as well as whole exome sequencing and whole genome sequencing (WGS) for study of EB (Takeichi et al., ; Vahidnezhad, Youssefian, Saeidian, et al., ; Vahidnezhad, Youssefian, Zeinali, et al., ). We have developed a NGS panel which consists of 21 genes associated with different skin fragility syndromes, including 19 genes shown to harbor mutations in patients with EB.…”

“…Recently, a number of NGS approaches have been adopted, including gene-targeted panels, as well as whole exome sequencing and whole genome sequencing (WGS) for study of EB (Takeichi et al, 2015;Vahidnezhad, Youssefian, Zeinali, et al, 2017). We have developed a NGS panel which consists of 21 genes associated with different skin fragility syndromes, including 19 genes shown to harbor mutations in patients with EB.…”

First report of COL7A1 mutations in two patients with recessive dystrophic epidermolysis bullosa from Peru

“…In the literature, no similar cases triggered by SEC have been reported, although tumour necrosis factor inhibitors have been reported to induce uveitis. 3 It may be difficult to clarify the pathomechanism of the symptoms of our case; however, it is noteworthy that similar events could happen when biologics are used to treat psoriasis. Recessive dystrophic epidermolysis bullosa (RDEB; OMIM #226600) is an autosomal recessive disorder characterized by skin fragility leading to trauma-induced blisters, which form beneath the basement membrane zone and heal with scarring and fibrosis.…”

The nature and biology of basement membranes

“…Skin blistering diseases also include those resulting from ruptures at the level or keratin (EB simplex, keratin gene mutations) and anchoring fibrils (EB dystrophica, collagen VII) [28,29]. Notably, collagen VII is elevated in patients with systemic sclerosis [43].…”