Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.
Hum Mutat
; 42(6): 762-776, 2021 06.
Article
in En
| MEDLINE
| ID: mdl-33847017
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 ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hereditary Sensory and Autonomic Neuropathies
/
Carrier Proteins
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Intellectual Disability
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Nerve Tissue Proteins
Type of study:
Diagnostic_studies
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Etiology_studies
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Guideline
/
Incidence_studies
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Observational_studies
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Prevalence_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Limits:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Language:
En
Journal:
Hum Mutat
Journal subject:
GENETICA MEDICA
Year:
2021
Document type:
Article
Affiliation country:
Alemania
Country of publication:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA