期刊
HUMAN MUTATION
卷 42, 期 6, 页码 762-776出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24206
关键词
Human Phenotype Ontology; neurodevelopmental disorder; sensory autonomic neuropathy; spastic paraplegia; TECPR2
资金
- German National Academic Foundation
- Bayer Foundation
- Deutsche Forschungsgemeinschaft (DFG) [PO2366/2-1]
- 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) [UM1 HG006542]
- NHGRI [K08 HG008986]
- 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 [5U54HG006542]
- Projekt DEAL
Bi-allelic TECPR2 variants are associated with a syndrome combining features of neurodevelopmental and neurodegenerative disorders, characterized by developmental delay, muscular hypotonia, and ataxia. Despite challenges in variant interpretation and pathogenicity classification, recommendations for reporting, assessment, and surveillance/treatment have been provided based on clinical, neuroimaging, and genetic data.
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.
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