A monoallelic two-hit mechanism in PLCD1 explains the genetic pathogenesis of hereditary trichilemmal cyst formation

Abstract Trichilemmal cysts are common hair follicle-derived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole exome sequencing of DNA from blood samples of five affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, we identified a combination of the Phospholipase C Delta 1 ( PLCD1) germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. Analysis of tissue from several cysts revealed that an additional somatic PLCD1 mutation on the same allele is required for cyst formation. In two different functional in vitro assays, we showed that the protein function of the cyst-specific PLCδ1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.