A cohort study published in JAMA Dermatology found new pathogenic variants for uncombable hair syndrome (UHS), a rare hair shaft anomaly with only 100 known cases, which can be used in molecular diagnostics and aid clinicians in UHS management.
Following their 2016 study, which identified the first-known UHS biallelic genetic variants, investigators were contacted by many clinicians and patients with information on additional possible UHS cases. They conducted a molecular genetic analysis using Sanger sequencing, and performed haplotype analyses for the 4 most commonly observed pathogenic variants in PAD13 using single-nucleotide polymorphism (SNP) chip data.
Investigators received EDTA blood samples, saliva and DNA from 89 unrelated index patients, and obtained DNA to screen an affected sibling or parent in 7 and 2 families, respectively.
In addition to the 18 patients with UHS from the 2016 study, investigators performed genetic screening on 89 unrelated individuals with suspected UHS (69 women and 20 men) and identified pathogenic variants in 69 of them: 67 with recurrent and/or novel pathogenic variants of PAD13 in either a homozygous or compound heterozygous state, and 2 who carried previously unreported compound heterozygous pathogenic variants in either TGM3 or TCHH. In 11 individuals with newly-discovered variants, there were 8 previously unreported pathogenic variants of PAD13, expanding the UHS spectrum of PAD13 to include 12 pathogenic variants in individuals from 20 countries. All individuals with pathogenic variants in PAD13, TGM3 or TCHH showed an autosomal recessive mode of inheritance.
The haplotype analysis for the 4 most common pathogenic PAD13 variants supported the thesis that variants likely descended from a respective common ancestor than from multiple independent occurrences.
The study was limited by the possibility that expression of some known UHS-associated genes remained undetected by the study’s sequencing approaches.
In 3 newly referred families, exome sequencing data revealed pathogenic variants in genes associated with the woolly hair phenotype, suggesting that woolly hair, with or without hypotrichosis, “may be mistaken for UHS by clinicians or affected individuals,” the study authors wrote. They therefore suggested that woolly hair “should be considered in the differential diagnosis of UHS.”
Disclosure: A study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Basmanav FB, Cesarato N, Kumar S, et al. Assessment of the genetic spectrum of uncombable hair syndrome in a cohort of 107 individuals. JAMA Dermatol. Published online August 31, 2022. doi:10.1001/jamadermatol.2022.2319