Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals
Authors: Basmanav F. Buket , Cesarato Nicole , Kumar Sheetal , Borisov Oleg , Kokordelis Pavlos , Ralser Damian J. , Wehner Maria , Axt Daisy , Xiong Xing , Thiele Holger , Dolgin Vadim , Gossmann Yasmina , Fricker Nadine , Dewenter Malin Katharina , Weller Karsten , Suri Mohnish , Reichenbach Herbert , Oji Vinzenz , Addor Marie-Claude , Ramirez Karla , Stewart Helen , Garcia Bartels Natalie , Weibel Lisa , Wagner Nicola , George Susannah , Kilic Arzu , Tantcheva-Poor Iliana , Stewart Alison , Dikow Nicola , Blaumeiser Bettina , Medvecz Márta , Blume-Peytavi Ulrike , Farrant Paul , Grimalt Ramon , Bertok Sara , Bradley Lisa , Eskin-Schwartz Marina , Birk Ohad Samuel , Bygum Anette , Simon Michel , Krawitz Peter , Fischer Christine , Hamm Henning , Fritz Günter , Betz Regina C. 
Published: August 2022

ImportanceUncombable 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.ObjectiveTo elucidate the genetic spectrum of UHS.Design, Setting, and ParticipantsThis 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 MeasuresClinical 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.ResultsThe 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 RelevanceThis 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.