BG01: Hair/tooth ectodermal dysplasia type 14 without hypohidrosis caused by biallelic TSPEAR variants

Z. Haider,¹ A. Jackson,^2,3 G. Ryan,⁴ S. Banka^2,3 and C. Moss¹

¹Birmingham Children’s Hospital, Birmingham, UK; ²Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK; ³Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, Manchester, UK; and ⁴West Midlands Genomic Medicine Centre, Birmingham, UK

Ectodermal dysplasias (EDs) are a highly heterogeneous group of genetic disorders associated with mutations in > 15 genes. However, the genetic basis of > 50% of ED conditions remains unknown (Wright JT, Fete M, Schneider H et al. Ectodermal dysplasias: classification and organization by phenotype, genotype and molecular pathway. Am J Med Genet A 2019; 179: 442–7). We report a boy with subtle features of ED for whom the recent discovery of a new ED gene led to a genetic diagnosis 9 years after his initial presentation. This now 13-year-old white boy was diagnosed at 4 years of age with ED on the basis of missing and conical-shaped teeth and dry, wiry, slow-growing hair. He was minimally dysmorphic with slightly protuberant ears but entirely normal skin, nails and sweating. There was early speech delay but normal hearing, no relevant family history and his parents were nonconsanguineous. Initial genetic testing revealed no pathogenic variants in the EDA or EDAR. In 2017 he was recruited, as a trio with both unaffected parents, to the 100,000 Genome Project. Initial analysis using PanelApp panel ‘ED without a known gene mutation v1.15’, revealed no pathogenic variants. Subsequent panel-agnostic reanalysis of whole-genome data revealed pathogenic compound heterozygous TSPEAR (p.Leu191Valfs*65 and p.Gly475Ser) variants. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, which is thought to regulate the Notch signalling pathway, important for the embryonic development of a stratified multilayer epidermis. Biallelic TSPEAR variants were recently identified to cause autosomal recessive ED (OMIM 618180, ED 14, hair/tooth type with or without hypohidrosis) characterized by hypodontia, conical teeth and abnormal hair texture. So far, TSPEAR-related ED has been reported in only five cases worldwide (Peled A, Sarig O, Samuelov L et at. Mutations in TSPEAR, encoding a regulator of Notch signalling, affect tooth and hair follicle morphogenesis. PLOS Genet 2016; 12: e1006369). The clinical features of this condition are subtle and there may be many other undiagnosed patients. Our patient now has an affected sister aged 2·5 years, and knowledge of her genetic diagnosis will aid management and counselling. TSPEAR was not present in ED gene panel v1.15 but is included in the latest version (v1.19). It is important to note that, with the discovery of new genes, earlier negative results should be revisited.