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

Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Broesse, Ines; Schubert, Susanna; O'Grady, Lauren; Zech, Michael; Srivastava, Siddharth; Sweetser, David A.; Dincer, Yasemin; Mall, Volker; Winkelmann, Juliane; Behrends, Christian; Darras, Basil T.; Graham, Robert J.; Jayakar, Parul; Byrne, Barry; Bar-Aluma, Bat El; Haberman, Yael; Szeinberg, Amir; Aldhalaan, Hesham M.; Hashem, Mais; Al Tenaiji, Amal; Ismayl, Omar; Al Nuaimi, Asma E.; Maher, Karima; Ibrahim, Shahnaz; Khan, Fatima; Houlden, Henry; Ramakumaran, Vijayalakshmi S.; Pagnamenta, Alistair T.; Posey, Jennifer E.; Lupski, James R.; Tan, Wen-Hann; ElGhazali, Gehad; Herman, Isabella; Munoz, Tatiana; Repetto, Gabriela M.; Seitz, Angelika; Krumbiegel, Mandy; Poli, Maria Cecilia; Kini, Usha; Efthymiou, Stephanie; Meiler, Jens; Maroofian, Reza; Alkuraya, Fowzan S.; Abou Jamra, Rami; Popp, Bernt; Ben-Zeev, Bruria und Ebrahimi-Fakhari, Darius (2021): Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. In: Human Mutation, Bd. 42, Nr. 6: S. 762-776

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 beta-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1059-7794
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198