Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype.

TSPEAR (chr. 21q22.3) encodes a protein involved in tooth development and is predominantly expressed in the enamel knot. Biallelic loss of function variants in TSPEAR cause ectodermal dysplasia, tooth agenesis and sensorineural hearing loss. However, the role of TSPEAR in auditory processes is unclear. This study aimed at better delineating the allelic and clinical spectrum of TSPEAR-associated disorders. We identified homozygous and compound heterozygous causative variants in TSPEAR [NM_144991.3] in 11 patients from seven families. Abnormalities in tooth number and shape (conical teeth and tooth agenesis with a variable number of missing teeth) were found in all affected individuals. Maxillary retrusion was present in 6/11. Manifestations in other ectodermal-derived organs were seen in a minority of patients. None of the individuals had hearing loss. We identified a total of 10 variants, of which seven have not been previously published, and analyzed the effect of missense variants to support their pathogenicity. Our results demonstrate that individuals with biallelic variants in TSPEAR show complete penetrance for dental manifestations, but not for other ectodermal abnormalities. TSPEAR-related disorder is more common than previously thought, while hearing loss is not a feature of the disease.