Abstract

The concept of “precision medicine” has been a mainstay in discourses about the future of medicine, although it was not until
the completion of the Human Genome Project that genetic associations to Mendelian diseases have risen dramatically. Since
genetic variations in most (85%) monogenic or oligogenic diseases reside in exons, whole-exome sequencing (WES) serves
as a pivotal tool in the identification of causative variants in genodermatoses and other diseases, leading to efficient and
timely diagnosis. Here, we share our current diagnosis protocol for genodermatoses using WES as a first-tier solution. Two
cases are presented to demonstrate the process of identifying germline variants and one case for a somatic variant. In the
first case, a germline missense mutation in COL7A1 (exon73:c.G6127A) was identified for a patient that presented with clinical
symptoms of dystrophic epidermolysis bullosa (DEB). Immunofluorescence study revealed decreased collagen VII expression in
the dermal-epidermal junction. In case 2, we detected a germline missense mutation in KRT16 (exon1:c.374A>G) in a patient with
palmoplantar keratoderma (PPK) and congenital pachyonychia. Sanger sequencing and segregation analysis confirmed the
variant detected in WES. For case 3, a patient with linear nevus comedonicus was found to have a somatic missense mutation
in NEK9 (exon4:c.500T>C), which was only detected in the lesional DNA sample. Thus, WES shows great potential as a diagnostic
tool for monogenic or oligogenic genodermatoses. Since omics is a technology-driven tool, we expect that reaching precision
medicine is ever closer.

KEYWORDS : Whole-exome sequencing, genodermatoses, precision medicine