Identification and characterisation of genes for hair disorders

Abstract

Hair disorders comprise conditions in which affected individuals display one or more of the following features: an absence or a reduced amount (e.g. hypotrichosis) of hair; an excessive amount of hair (e.g. hypertrichosis); abnormal hair structure (e.g. uncombable hair syndrome, UHS); or abnormal hair growth (e.g. short anagen hair, SAH). Hair disorders develop as a consequence of genetic and/or environmental factors. The nature of the genetic influences can be either: i) direct causality as in the case of monogenic diseases, as in UHS or hypotrichosis; or ii) genetic susceptibility, as in male pattern hair loss (MPHL) also termed androgenetic alopecia. While causal or susceptibility genes have already been identified for some hair phenotypes, others still await molecular genetic elucidation. <br /> Therefore, the primary aim of the research described in the present thesis was to identify novel variants and/or genes associated with hair disorders. <br /> Within the context of a total of three separate studies, we performed Sanger and/or whole exome sequencing in DNA from patients affected by clinically diverse hair disorders, namely, hypotrichosis, UHS, and SAH. We identified novel pathogenic variants in genes that had already been associated with hypotrichosis and UHS and, for the first time, elucidated the genetic background of SAH by identifying a novel gene associated with its development. In detail, we identified novel pathogenic variants in LSS in four individuals affected by hypotrichosis with or without intellectual disability. We identified novel pathogenic variants in PADI3, TGM3, and TCHH, three genes associated to UHS, and delineated the mutational spectrum of UHS in a large cohort of 107 individuals. We performed molecular genetic analyses in a cohort of 48 individuals with SAH, and we discovered rare or low-frequency WNT10A variants in mono- or bi-allelic state in 20 of them. Using population-based genetic data we demonstrated the significant enrichment of WNT10A variants in individuals with SAH and discovered that two of the SAH-associated WNT10A variants are also associated with the risk of developing MPHL and partially explain the known association between WNT10A and MPHL. <br /> With these results, we have expanded knowledge on genetic hair disorders. In particular, we have: i) broadened the genetic spectrum of LSS-associated hypotrichosis; ii) delineated the mutational spectrum of UHS; and iii) unravelled that SAH has a genetic component by showing its association with WNT10A variants.