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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 m

Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture. Author summary Based on genome-wide genotype data on over 1000 samples from eleven ethnic groups present in Iran and by comparison to reference data sets of both extant populations and ancient DNA samples, we show that the Iranian population comprises distinct genetic variation with respect to populations in close geographic proximity, a cluster of genetically largely overlapping ethnic groups as well as a number of strongly admixed groups. These observations, also corroborated by f3 migration statistics and other approaches, indicate genetic continuity of and limited influx into the cluster groups over several millennia, despite Iran's geographic position at a crossroads in West Asia. They also suggest, correspondingly, several instances of language adoption instead of demic replacement in the past. Future human genetic studies, both with a focus on population and medical genetics, will have to consider differences in heterogeneity, consanguinity and degree of admixtur