Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability

PURPOSE: Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we aim to provide a comprehensive clinical description and variant interpretation framework. METHODS: Through an international collaboration, we identified 13 individuals from 12 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data of this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. RESULTS: A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 59%. We evaluated 14 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains difficult. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi population. CONCLUSION: Based on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.