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

Autor: Henry Houlden, David A. Sweetser, Hesham Aldhalaan, Barry J. Byrne, Bruria Ben-Zeev, Gabriela M. Repetto, Bernt Popp, Yasemin Dincer, Karima Maher, Reza Maroofian, Omar Ismayl, Fowzan S. Alkuraya, Susanna Schubert, Wen-Hann Tan, Jens Meiler, Usha Kini, Parul Jayakar, Fatima Khan, Darius Ebrahimi-Fakhari, Stephanie Efthymiou, Gehad ElGhazali, Mais Hashem, Vijayalakshmi Salem Ramakumaran, Volker Mall, Robert J. Graham, Bat El Bar-Aluma, Maria Cecilia Poli, Rami Abou Jamra, Barbara Brechmann, Asma E. Al Nuaimi, Gali Heimer, Sonja Neuser, Amir Szeinberg, Ines Brösse, Christian Behrends, Angelika Seitz, Mandy Krumbiegel, Jennifer E. Posey, Amal Al Tenaiji, Lauren O’Grady, Michael Zech, Siddharth Srivastava, James R. Lupski, Basil T. Darras, Isabella Herman, Alistair T. Pagnamenta, Juliane Winkelmann, Shahnaz Ibrahim, Yael Haberman, Tatiana Muñoz
Rok vydání: 2020
Předmět:
Male
Models
Molecular
Ataxia
Adolescent
Protein Conformation
Population
Mutation
Missense
Nerve Tissue Proteins
Neuroimaging
Disease
Biology
Bioinformatics
Cohort Studies
03 medical and health sciences
Neurodevelopmental disorder
Intellectual Disability
Human Phenotype Ontology
Intellectual disability
Hereditary sensory and autonomic neuropathy
Genetics
medicine
Missense mutation
Humans
Family
Global developmental delay
Hereditary Sensory and Autonomic Neuropathies
education
Child
Genetics (clinical)
030304 developmental biology
education.field_of_study
0303 health sciences
business.industry
030305 genetics & heredity
Infant
Hyporeflexia
medicine.disease
Magnetic Resonance Imaging
Pedigree
ddc
Cross-Sectional Studies
Phenotype
Child
Preschool
Female
medicine.symptom
business
Carrier Proteins
ISSN: 1098-1004
Popis: PURPOSEBi-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.METHODSThrough 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.RESULTSA 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.CONCLUSIONBased 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.CONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.
Databáze: OpenAIRE
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