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 |
Journal | Hum Mutat |
Volume | 42 |
Issue | 6 |
Pagination | 762-776 |
Date Published | 2021 Jun |
ISSN | 1098-1004 |
Keywords | Adolescent, Carrier Proteins, Child, Child, Preschool, Cohort Studies, Cross-Sectional Studies, Family, Female, Hereditary Sensory and Autonomic Neuropathies, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Models, Molecular, Mutation, Missense, Nerve Tissue Proteins, Neuroimaging, Pedigree, Phenotype, Protein Conformation |
Abstract | 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. |
DOI | 10.1002/humu.24206 |
Alternate Journal | Hum Mutat |
PubMed ID | 33847017 |
Grant List | UM1 HG006542 / HG / NHGRI NIH HHS / United States K08 HG008986 / HG / NHGRI NIH HHS / United States U54 HG006542 / HG / NHGRI NIH HHS / United States |
Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.
Similar Publications
Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample. Sci Rep. 2024;14(1):6385. | .
FAIR Header Reference genome: a TRUSTworthy standard. Brief Bioinform. 2024;25(3). | .
Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes. Circ Res. 2024;134(7):842-854. | .