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Neuser, S.* ; Brechmann, B.* ; Heimer, G.* ; Brösse, I.* ; Schubert, S.* ; O'Grady, L.* ; Zech, M. ; Srivastava, S.* ; Sweetser, D.A.* ; Dincer, Y.* ; Mall, V.* ; Winkelmann, J. ; Behrends, C.* ; Darras, B.T.* ; Graham, R.J.* ; Jayakar, P.* ; Byrne, B.* ; El Bar-Aluma, B.* ; Haberman, Y.* ; Szeinberg, A.* ; Aldhalaan, H.M.* ; Hashem, M.* ; Tenaiji, A.A.* ; Ismayl, O.* ; Al Nuaimi, A.E.* ; Maher, K.* ; Ibrahim, S.* ; Khan, F.* ; Houlden, H.* ; Ramakumaran, V.S.* ; Pagnamenta, A.T.* ; Posey, J.E.* ; Lupski, J.R.* ; Tan, W.H.* ; ElGhazali, G.* ; Herman, I.* ; Muñoz, T.* ; Repetto, G.M.* ; Seitz, A.* ; Krumbiegel, M.* ; Cecilia Poli, M.* ; Kini, U.* ; Efthymiou, S.* ; Meiler, J.* ; Maroofian, R.* ; Alkuraya, F.S.* ; Jamra, R.A.* ; Popp, B.* ; Ben-Zeev, B.* ; Ebrahimi-Fakhari, D.*

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

Hum. Mutat. 42, 762-776 (2021)
Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 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. 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 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. 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Tecpr2 ; Human Phenotype Ontology ; Neurodevelopmental Disorder ; Sensory Autonomic Neuropathy ; Spastic Paraplegia; Drosophila-melanogaster; Autophagy; Tecpr2; Variants; Prediction; Genomics; Mutation; Program
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Zeitschrift Human Mutation
Quellenangaben Band: 42, Heft: 6, Seiten: 762-776 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen Projekt DEAL
Bayer Foundation
Deutsche Forschungsgemeinschaft (DFG)
CureAP4 Foundation
CureSPG50 Foundation
Spastic Paraplegia Foundation
Thrasher Research Fund
Astellas Pharmaceutical Inc.
MitoBridge Inc.
US NIH National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI)
NHGRI
National Institute for Health Research
NHS England
Wellcome Trust
Cancer Research UK
Medical Research Council
Baylor-Hopkins Center for Mendelian Genomics through National Human Genome Research Institute
German National Academic Foundation
DOI 10.1002/humu.24206
WOS ID WOS:000648919800001
Scopus ID 85105550925
PubMed ID 33847017
Erfassungsdatum 2021-06-07
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