Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Brösse, 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; Muñoz, 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; Ebrahimi-Fakhari, Darius     «

Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Brösse, 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; Ramak...     »

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.      «

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 st...     »