{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:47:38Z","timestamp":1791229658596,"version":"4.1.0"},"reference-count":10,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2022,11,1]]},"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>To elucidate the genetic spectrum of UHS.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>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.<\/jats:p><\/jats:sec>Results<\/jats:title>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<\/jats:italic>, TGM3<\/jats:italic>, or TCHH<\/jats:italic> (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<\/jats:italic>. The 2 most commonly observed PADI3<\/jats:italic> variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3<\/jats:italic> alleles in total, respectively. Two individuals carried pathogenic variants in TGM3<\/jats:italic>, and 2 others carried pathogenic variants in TCHH<\/jats:italic>. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3<\/jats:italic> gene.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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<\/jats:italic>, TCHH<\/jats:italic>, and TGM3<\/jats:italic> may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2022.2319","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T15:33:44Z","timestamp":1661960024000},"page":"1245","source":"Crossref","is-referenced-by-count":17,"title":["Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals"],"prefix":"10.1001","volume":"158","author":[{"given":"F. Buket","family":"Basmanav","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Cesarato","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheetal","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Borisov","sequence":"additional","affiliation":[{"name":"Institute for Genomic Statistics and Bioinformatics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Xiong","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Dolgin","sequence":"additional","affiliation":[{"name":"Genetics Institute at Soroka University Medical Center, Beer-Sheva, Israel"},{"name":"Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases at the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel"},{"name":"National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmina","family":"Gossmann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Fricker","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin Katharina","family":"Dewenter","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Weller","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Charit\u00e9-Universit\u00e4tsmedizin 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