Supplementary Material for: A Novel Pathogenic TSPEAR Variant in a Family with Clinical Variability: Definition of Dental Anomalies and Review of the Literature

Background: Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders marked by impaired development of multiple tissue derivatives originating from the human ectoderm, including teeth, hair, nails, and sweat glands. Advances in next-generation sequencing technology have facilitated the identification of novel genes, such as TSPEAR, contributing to the emergence of the Ectodermal Dysplasia-14 of the hair/tooth type (ECTD14) phenotype, primarily characterized by hypotrichosis, hypodontia, and dysmorphic features.
Methods: Five individuals who displayed ectodermal dysplasia and/or teeth loss were included in the study. Exome sequencing (ES) was performed in the index case, and Sanger sequence analysis was carried out to detect the carrier status in parents and relatives.
Results: We identified a novel biallelic frameshift TSPEAR variant [(NM_144991.2, c.1594_1595insA, p.(Phe532TyrfsTer26)] in two siblings who displayed oligodontia, sparse hair, and facial dysmorphism. The remaining heterozygous carriers manifested early tooth loss with nonsyndromic isolated oligodontia.
Conclusion: This study has identified individuals carrying biallelic and heterozygous TSPEAR variants, where heterozygous carriers often exhibit nonsyndromic tooth agenesis. Moreover, the presence of inter- and intrafamilial variability emerges as a notable feature of the disease. This understanding underscores the complexity of the disease and the importance of considering genetic variability when diagnosing and managing affected individuals