Importance Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests
during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed
flat. Only about 100 known cases have been reported so far. Objective To elucidate
the genetic spectrum of UHS. Design, Setting, and Participants This cohort study includes
107 unrelated index patients with a suspected diagnosis of UHS and family members
who were recruited worldwide from January 2013 to December 2021. Participants of all
ages, races, and ethnicities were recruited at referral centers or were enrolled on
their own initiative following personal contact with the authors. Genetic analyses
were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures
Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping
of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling.
Descriptive statistics, such as frequency counts, were used to describe the distribution
of identified pathogenic variants and genotypes. Results The genetic characteristics
of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%]
female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes
that encode functionally related hair shaft proteins). Molecular genetic findings
from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals,
the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly
observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3
alleles in total, respectively. Two individuals carried pathogenic variants in TGM3,
and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder
effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions
and Relevance This cohort study extends and gives an overview of the genetic variant
spectrum of UHS based on molecular genetic analyses of the largest worldwide collective
of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only
be made by physical examination of the patient and confirmed by microscopical examination
of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may
open a new avenue for clinicians and affected individuals by introducing molecular
diagnostics for UHS.
