Expanding the mutational spectrum of TSPEAR in ectodermal dysplasia type 14: a familial case study.
Background: Ectodermal dysplasia (ED) encompasses a heterogeneous group of genetic disorders affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands. Among these, mutations in TSPEAR (Thrombospondin-type laminin G domain and epilepsy-associated repeats) have been implicated in autosomal recessive ectodermal dysplasia type 14 (ED14) (OMIM 618180), predominantly manifesting with dental anomalies and hair dysplasia. However, the mutational spectrum of TSPEAR remains incompletely characterized. Methods: Two female siblings (ID#1 and ID#4) were clinically evaluated for ED. Genetic analysis, including next-generation sequencing (NGS) and Sanger validation, was conducted to identify TSPEAR variants. A segregation study confirmed inheritance patterns within the family. Results: Both affected siblings exhibited hallmark features of TSPEAR-related ED14, including oligodontia with dysmorphic, pointed maxillary central incisors. Hair thinning and cutaneous angiomas were prominent in ID#4. Genetic analysis identified two compound heterozygous variants in TSPEAR: c.543-1G>A, a splice-site mutation likely disrupting mRNA processing, and NM_144991.2:c.1251G>C(p.Gln417His), a missense variant predicted to be deleterious. Segregation analysis confirmed their maternal and paternal inheritance. A third sibling, ID#5, was a heterozygous carrier without clinical manifestations. Conclusion: This study contributes to the expanding understanding of TSPEAR-related ED14 by providing novel genotype-phenotype correlations. The identification of a splice-site variant and a missense mutation underscores the functional importance of TSPEAR in ectodermal development. These findings highlight the necessity of molecular testing for accurate diagnosis and genetic counseling in families affected by rare ectodermal dysplasias.