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 ( c.1285G>T, and c.3373G>A; c.1828A>G) and five previously reported variants ( c.6209G>A, and c.1573C>T; c.676insC; c.151insG; 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 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. read more
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of ectopic mineralization and fragmentation of elastic fibers in skin, eyes, cardiovascular and digestive system. PXE is caused by sequence variants in ABCC6, which encodes multidrug resistance-associated protein 6 (MRP6, also known as the ABCC6 protein). MRP6 is an important regulator of inorganic plasma pyrophosphate that acts as an inhibitor of ectopic mineralization observed in PXE patients with low inorganic plasma pyrophosphate levels. The current study was designed to investigate underlying genetic defect in two unrelated Pakistani families affected with PXE. Whole exome sequencing followed by Sanger sequencing was performed to identify causative variants. A novel homozygous frameshift variant (c.1799_1805dupGTCTGGT) was identified in one family and two previously reported missense variants (c.2294G > A and c.2974G > A) in compound heterozygous form in the other family. We identified ABCC6 variants that are likely cause of the PXE disease in the tested families. Genetic analysis of these families could be useful for pre-symptomatic diagnosis and genetic counselling of the affected families. read more
