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

PURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus.METHODSThrough an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.RESULTSA 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 52%. We evaluated 17 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 challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations.CONCLUSIONBased 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.CONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.