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 characterised 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 Here, molecular genetic investigations were performed 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 complaint of short, non-growing 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 the UK Biobank data. Results The analyses revealed that 20 individuals (∼40%) 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 (ED). A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and a regression of the fronto-parietal 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 biological 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.