Pathogenic variants identified in individuals with uncombable hair syndrome in JAMA study

A new study published in the Journal of American Medical Association identifies a new pathogenic variant in patients with uncombable hair syndrome (UHS). This study expands the known genetic variation spectrum of UHS, based on analysis of the world's largest affected population.

Uncombable hair syndrome is among rare hair shaft abnormality that appears in infancy and is characterized by dry, frizzy, limp hair that cannot be combed smoothly. Therefore, Buket Basmanav and his peers undertook this study to elucidate the genetic spectrum of UHS.

This cohort included 107 unrelated index patients with suspected UHS diagnosis and their families recruited from January 2013 to December 2021 worldwide. Participants of all ages, races and ethnicities were either recruited from a referral center or contacted personally with the authors on their own initiative. Genetic analysis was performed in Germany from January 2014 to December 2021. Clinical photography, Sanger or whole exome sequencing, and array-based genotyping of DNA extracted from blood or saliva samples, and three-dimensional protein modeling were the main goals. Descriptive statistics such as frequency counts were used to describe the distribution of identified pathogenic variants and genotypes.

The main highlights of this study were:

1. Genetic characterization of UHS patients was determined in 80 (74.8%) of 107 index patients (82 [76.6%] female) who harbor biallelic pathogenic variants in PADI3, TGM3, or TCHH. Her molecular genetic findings for 11 of these 80 have already been published.

2. In 76 (71.0%) individuals, the UHS phenotype was associated with a PADI3 pathogenic variant.

3. The two most commonly observed her PADI3 variants account for 73 (48.0%) and 57 (37.5%), respectively, of a total of 152 her PADI3 variant alleles.

4. Two had a pathogenic variant in TGM3 and the other two had a pathogenic variant in TCHH.

5. Haplotype analysis showed founder effects of the four most frequently observed pathogenic variants in the PADI3 gene.

This cohort study expanded the UHS pathogen variant spectrum and establish that PADI3 was most commonly associated with this rare hair phenotype. Our current results also indicate that the four most commonly observed pathogenic PADI3 variants are much more likely to have descended from their respective common ancestors than to have independently occurred multiple times.

Reference: 

Basmanav, F. B., Cesarato, N., Kumar, S., Borisov, O., Kokordelis, P., Ralser, D. J., Wehner, M., Axt, D., Xiong, X., Thiele, H., Dolgin, V., Gossmann, Y., Fricker, N., Addor, M.-C., … Betz, R. C. (2022). Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals. In JAMA Dermatology. American Medical Association (AMA). https://doi.org/10.1001/jamadermatol.2022.2319