%0 Journal Article
%T Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.
%A Neuser S
%A Brechmann B
%A Heimer G
%A Brösse I
%A Schubert S
%A O'Grady L
%A Zech M
%A Srivastava S
%A Sweetser DA
%A Dincer Y
%A Mall V
%A Winkelmann J
%A Behrends C
%A Darras BT
%A Graham RJ
%A Jayakar P
%A Byrne B
%A Bar-Aluma BE
%A Haberman Y
%A Szeinberg A
%A Aldhalaan HM
%A Hashem M
%A Al Tenaiji A
%A Ismayl O
%A Al Nuaimi AE
%A Maher K
%A Ibrahim S
%A Khan F
%A Houlden H
%A Ramakumaran VS
%A Pagnamenta AT
%A Posey JE
%A Lupski JR
%A Tan WH
%A ElGhazali G
%A Herman I
%A Muñoz T
%A Repetto GM
%A Seitz A
%A Krumbiegel M
%A Poli MC
%A Kini U
%A Efthymiou S
%A Meiler J
%A Maroofian R
%A Alkuraya FS
%A Abou Jamra R
%A Popp B
%A Ben-Zeev B
%A Ebrahimi-Fakhari D
%J Hum Mutat
%V 42
%N 6
%D 06 2021
%M 33847017
%F 4.7
%R 10.1002/humu.24206
%X 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.