F Buket Basmanav1, Nicole Cesarato1, Sheetal Kumar1, Oleg Borisov2, Pavlos Kokordelis1, Damian J Ralser1, Maria Wehner1, Daisy Axt1, Xing Xiong1, Holger Thiele3, Vadim Dolgin4,5,6, Yasmina Gossmann1, Nadine Fricker1, Malin Katharina Dewenter7, Karsten Weller8, Mohnish Suri9, Herbert Reichenbach10, Vinzenz Oji11, Marie-Claude Addor12, Karla Ramirez13, Helen Stewart14, Natalie Garcia Bartels8, Lisa Weibel15,16, Nicola Wagner17, Susannah George18, Arzu Kilic19, Iliana Tantcheva-Poor20, Alison Stewart21, Nicola Dikow22, Bettina Blaumeiser23, Márta Medvecz24, Ulrike Blume-Peytavi8, Paul Farrant18, Ramon Grimalt25, Sara Bertok26, Lisa Bradley27, Marina Eskin-Schwartz4, Ohad Samuel Birk4, Anette Bygum28,29, Michel Simon30,31, Peter Krawitz2, Christine Fischer22, Henning Hamm32, Günter Fritz33, Regina C Betz1. 1. Institute of Human Genetics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany. 2. Institute for Genomic Statistics and Bioinformatics, Medical Faculty & University Hospital Bonn, University of Bonn, Bonn, Germany. 3. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 4. Genetics Institute at Soroka University Medical Center, Beer-Sheva, Israel. 5. 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. 6. National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 7. Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 8. Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 9. Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, England, United Kingdom. 10. MVZ Mitteldeutscher Praxisverbund Humangenetik, Praxis Leipzig, Leipzig, Germany. 11. Department of Dermatology, University of Münster, Münster, Germany. 12. Department of Woman-Mother-Child, University Hospital Center CHUV CH 1011, Lausanne, Switzerland. 13. Neurología Pediátrica, Division de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. 14. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, England, United Kingdom. 15. Pediatric Dermatology Department, University Children's Hospital Zurich, University Hospital Zurich, Zurich, Switzerland. 16. Dermatology Department, University Hospital Zurich, Zurich, Switzerland. 17. Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany. 18. Dermatology Department, Brighton General Hospital, University Hospitals Sussex NHS Foundation Trust, Brighton, England, United Kingdom. 19. Department of Dermatology, Faculty of Medicine, Balıkesir University, Balıkesir, Turkey. 20. Department of Dermatology and Venereology, University Hospital of Cologne, Cologne, Germany. 21. Sheffield Clinical Genetics Service, Sheffield Children's Hospital, South Yorkshire, England, United Kingdom. 22. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany. 23. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. 24. Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary. 25. Universitat Internacional de Catalunya, Barcelona, Spain. 26. Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre, Ljubljana, Slovenia. 27. Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin, Dublin, Ireland. 28. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 29. Clinical Institute, University of Southern Denmark, Odense, Denmark. 30. Toulouse Institute for Infectious and Inflammatory diseases, Toulouse University, Toulouse, France. 31. CNRS, Inserm, Paul Sabatier Toulouse III University, Toulouse, France. 32. Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany. 33. Department of Cellular Microbiology, University of Hohenheim, Stuttgart, Germany.
Abstract
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.
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.
Authors: F Buket Ü Basmanav; Laura Cau; Aylar Tafazzoli; Marie-Claire Méchin; Sabrina Wolf; Maria Teresa Romano; Frederic Valentin; Henning Wiegmann; Anne Huchenq; Rima Kandil; Natalie Garcia Bartels; Arzu Kilic; Susannah George; Damian J Ralser; Stefan Bergner; David J P Ferguson; Ana-Maria Oprisoreanu; Maria Wehner; Holger Thiele; Janine Altmüller; Peter Nürnberg; Daniel Swan; Darren Houniet; Aline Büchner; Lisa Weibel; Nicola Wagner; Ramon Grimalt; Anette Bygum; Guy Serre; Ulrike Blume-Peytavi; Eli Sprecher; Susanne Schoch; Vinzenz Oji; Henning Hamm; Paul Farrant; Michel Simon; Regina C Betz Journal: Am J Hum Genet Date: 2016-11-17 Impact factor: 11.025