Interpretation of genomic sequence variants in genetic skin diseases: A primer for clinicians.

Abstract

Over 1,000 heritable disorders have cutaneous manifestations, some of them being syndromic in association with extracutaneous manifestations, while others being limited to the skin. The genetic basis of many of these conditions has been deciphered, and mutation analysis by next-generation sequencing approaches, including whole-exome sequencing, whole-genome sequencing, and whole-transcriptome analysis, are now increasingly part of the diagnostic process. Besides confirming the diagnosis, information on the specific mutations can be used for sub-classification with prognostication and identification of carriers leading to accurate genetic counseling, and it also forms the basis for prenatal testing and preimplantation genetic diagnosis. Furthermore, ongoing therapeutics developments for heritable skin diseases are often allele-specific, necessitating the knowledge of the specific genes and mutations. While practicing clinicians increasingly employ molecular diagnostics for heritable skin diseases, they often lack sufficient knowledge of how to interpret the implications of the mutations with precision. The purpose of this primer is to provide an overview of mutation detection strategies and how to interpret the genetic information for improved diagnostics and management of the patients.