Genetic principles related to neurocutaneous disorders

Abstract

A detailed understanding of genetics is critical to the diagnosis, management, and prognostication of neurocutaneous disorders. Inheritance patterns can provide a key to the identification of different neurocutaneous disorders. Autosomal dominant disorders, like neurofibromatosis type 1 and tuberous sclerosis complex, affect males and females equally and are typically seen in every generation of a pedigree due to pathogenic changes to one copy of a gene on a somatic chromosome. Autosomal recessive disorders, such as ataxia-telangiectasia, affect males and females equally but typically skip generations on pedigrees as there needs to be a pathogenic variant of the gene on each of the pair of somatic chromosomes. X-linked disorders such as incontinentia pigmenti and Fabry disease primarily affect males or affect them more severely, but in the case of incontinentia pigmenti, the condition is lethal in males and only females are noted to be affected. The pathogenic variant that is disease causing is on the X sex chromosome, of which females have two and males have one. Somatic mosaic disorders like Sturge Weber syndrome are due to pathogenic variants only in a subset of cells post-fertilization and are not present in gametes, and so are not passed on to the next generation. Conditions that are a result of germline mosaicism are usually identified as autosomal dominant conditions that have not been present in the family prior to a single child being affected, with suspicion strengthening if siblings are diagnosed with the same condition. Regardless of the suspected inheritance pattern, it is essential to consider the ethical implications of genetic testing, including family planning, discovery of consanguinity, disclosure to other potentially affected family members, and diagnostic uncertainty.