Mosaic disorders affecting pigmentation – part 2: how to make a genetic diagnosis

Mosaic disorders affecting pigmentation are a large group of different, rare diseases that present with hypo- and/or hyperpigmented birthmarks. These can carry associated risks such as involvement of other organ systems, a predisposition to cancer and the possibility of transmission to future offspring as germline disease. This review draws on the clinical and genetic discoveries of the last decade to discuss how to make a genetic diagnosis in mosaic disorders affecting pigmentation. Practicalities reviewed include how to take the right samples for testing and how to process the samples correctly, while key concepts include understanding variant allele frequency, variants of uncertain significance and sensitivity of genetic testing. It then goes on to demonstrate how to use the clinical classification established in part 1 of this two-part review to decide which genetic tests to perform and in which order. All currently known genetic causes of mosaic disorders affecting pigmentation are detailed, along with which genes have variants with the potential for germline transmission to the next generation.