Identification and characterisation of genes for hair disorders

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. Therefore, the primary aim of the research described in the present thesis was to identify novel variants and/or genes associated with hair disorders. 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. 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

A new de novo heterozygous missense mutation in the desmoplakin gene, causing Naxos and Carvajal disease, associating oligodontia and nail fragility

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Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss

Abstract Background Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown. Objectives To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition. Methods Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. Results Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL. Conclusions Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus

Apparent Missense Mutation in COL7A1 Causes a Severe Form of Recessive Dystrophic Epidermolysis Bullosa via Effects on Splicing

Dystrophic epidermolysis bullosa is an inherited skin disorder characterized by fragile skin that is prone to blistering. We report here a consanguineous Pakistani family with two siblings, in whom a severe recessive dystrophic epidermolysis bullosa was suspected. Using whole-exome sequencing for one sibling, the homozygous base substitution c.7249C>G in COL7A1 was identified, and could be confirmed in the other sibling by Sanger sequencing. In our exome data, this mutation was annotated as a missense substitution (p.Gln2417Glu), but in silico tools indicated a possible effect on splicing. Using the ExonTrap vector it was verified that the mutation leads to activation of a cryptic donor splice site, which leads to loss of 26 nucleotides, and a frameshift event predicted to result in a truncated protein (p.Q2417Sfs*57). The present report describes an apparent COL7A1 missense substitution with an unexpected consequence on splicing that leads to a severe recessive dystrophic epidermolysis bullosa phenotype