Abstract
DST encodes bullous pemphigoid antigen-1 (BPAG1), a protein with eight tissue-specific isoforms expressed in the skin, muscle, brain, and nerves. Accordingly, mutations in this gene are associated with epidermolysis bullosa simplex (EBS) and hereditary sensory and autonomic neuropathy type 6 (HSAN-VI). The genotypic spectrum is attested to by 19 distinct mutations but genotype-phenotype correlation for both disorders is not well established. In this study, we performed next-generation sequencing (NGS) on two families with different phenotypic presentations, one fetus (P1) with musculoskeletal and neurological malformations established by prenatal ultrasound and family history, and a 15-year-old female (P2) with skin blistering. P1 had a novel homozygous nonsense mutation, DST: NM_001144769, c.3805C>T, p.R1269* within a region of homozygosity (ROH). This mutation resides within the plakin domain of BPAG1 and ablates all isoforms of this protein, leading to novel ex tracutaneous phenotypes consistent with HSAN-VI in P1. P2 had a recurrent homozygous mutation DST: NM_001723.7, c.3370C>T, p.Gln1124* that presented with giant, trauma-induced skin blisters without extracutaneous involvement. This mutation is located within the coiled-coil domain present on the skin isoform of DST, BPGA1-e, associated with EBS. In summary, we report two families with pathogenic DST variants and expand the spectrum of DST genotype and phenotypes.
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