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.

Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals

Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany

Institute for Genomic Statistics and Bioinformatics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany

Cologne Center for Genomics, University of Cologne, Cologne, Germany

Genetics Institute at Soroka University Medical Center, Beer-Sheva, Israel

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

National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany

Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, England, United Kingdom

MVZ Mitteldeutscher Praxisverbund Humangenetik, Praxis Leipzig, Leipzig, Germany

Department of Dermatology, University of Münster, Münster, Germany

Department of Woman-Mother-Child, University Hospital Center CHUV CH 1011, Lausanne, Switzerland

Neurología Pediátrica, Division de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, England, United Kingdom

Pediatric Dermatology Department, University Children’s Hospital Zurich, University Hospital Zurich, Zurich, Switzerland

Dermatology Department, University Hospital Zurich, Zurich, Switzerland

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

Dermatology Department, Brighton General Hospital, University Hospitals Sussex NHS Foundation Trust, Brighton, England, United Kingdom

Department of Dermatology, Faculty of Medicine, Balıkesir University, Balıkesir, Turkey

Department of Dermatology and Venereology, University Hospital of Cologne, Cologne, Germany

Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, South Yorkshire, England, United Kingdom

Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary

Universitat Internacional de Catalunya, Barcelona, Spain

Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre, Ljubljana, Slovenia

Department of Clinical Genetics, Children’s Health Ireland (CHI) at Crumlin, Dublin, Ireland

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

Clinical Institute, University of Southern Denmark, Odense, Denmark

Toulouse Institute for Infectious and Inflammatory diseases, Toulouse University, Toulouse, France

CNRS, Inserm, Paul Sabatier Toulouse III University, Toulouse, France

Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany

Department of Cellular Microbiology, University of Hohenheim, Stuttgart, Germany