TSPEAR (thrombospondin type laminin G domain and EAR repeats) is a gene on chromosome 21 with critical roles in ectodermal development. Primary Function: TSPEAR regulates tooth and hair follicle morphogenesis through Notch signaling pathway regulation 1 and may contribute to auditory system development 2. Mechanism: TSPEAR functions as an extracellular matrix-dependent signaling regulator, orthologous to Drosophila Closca 3. The protein contains a β-propeller domain; pathogenic missense variants likely destabilize this structure 3. Expression is highly restricted to enamel knots during tooth development, with suggested functional interaction with Wnt10a signaling 3. Disease Relevance: Biallelic TSPEAR variants cause autosomal recessive ectodermal dysplasia 14 (ARED14), characterized primarily by dental anomalies including conical tooth cusps and hypodontia, hair dysplasia, and nail abnormalities 34. TSPEAR also contributes to selective tooth agenesis 5. The non-Finnish European population carrier rate is approximately 1/140, making ARED14 one of the most common autosomal recessive ectoderm dysplasias 3. Clinical Significance: Early genetic diagnosis enables timely multidisciplinary management involving orthodontic, prosthetic, and surgical interventions 5. Multiple founder variants exist across populations, with non-Finnish European variants originating approximately 12,000 years ago 3.