|Title||Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Neuser, S, Brechmann, B, Heimer, G, Brösse, I, Schubert, S, O'Grady, L, Zech, M, Srivastava, S, Sweetser, DA, Dincer, Y, Mall, V, Winkelmann, J, Behrends, C, Darras, BT, Graham, RJ, Jayakar, P, Byrne, B, Bar-Aluma, BEl, Haberman, Y, Szeinberg, A, Aldhalaan, HM, Hashem, M, Tenaiji, AAl, Ismayl, O, Nuaimi, AEAl, Maher, K, Ibrahim, S, Khan, F, Houlden, H, Ramakumaran, VS, Pagnamenta, AT, Posey, JE, Lupski, JR, Tan, W-H, ElGhazali, G, Herman, I, Muñoz, T, Repetto, GM, Seitz, A, Krumbiegel, M, Poli, MCecilia, Kini, U, Efthymiou, S, Meiler, J, Maroofian, R, Alkuraya, FS, Jamra, RAbou, Popp, B, Ben-Zeev, B, Ebrahimi-Fakhari, D|
|Date Published||2021 Jun|
Bi-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. Through 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. 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 magnetic resonance imaging 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 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. 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.
|Alternate Journal||Hum Mutat|