NKX2 ‐1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea
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Le résumé fourni par la source
BACKGROUND: NKX2-1-related disorders (NKX2-1-RDs) classically present with a triad of neurological, endocrine, and pulmonary manifestations, including benign hereditary chorea. However, in a fraction of patients, NKX2-1 coding variants are not detected, and variants outside the NKX2-1 locus have been reported. OBJECTIVE: The objective of this study was to evaluate the clinical spectrum and frequency of regulatory variants in NKX2-1-RDs. METHODS: Eight families carrying structural variants near NKX2-1 without disruption of the coding sequence were recruited, and clinical data were systematically collected. Regulatory activity was assessed using EpiMap data. Frequency and diagnostic yield were evaluated in a cohort of 26 individuals with molecularly confirmed NKX2-1-RD. RESULTS: Eight families comprising 13 affected individuals were identified: five with downstream deletions and three with complex structural rearrangements. Neurological manifestations were universal, including chorea, myoclonus, and ataxia, while cognitive or behavioral abnormalities occurred in a subset. Individuals with deletions rarely presented extraneurological features, whereas all carriers of complex structural variants showed the complete triad. All deletions and breakpoints were located downstream of NKX2-1. The core shared deleted region showed open chromatin and H3K27ac peaks in fetal brain, lung, and thyroid tissues, suggesting regulatory activity. Regulatory variants accounted for 27% of NKX2-1-RD diagnoses in our institutions. Exome sequencing combined with copy-number variant analysis captured 92% of diagnoses when MBIP was evaluated as a target for downstream variants. CONCLUSIONS: Downstream regulatory variants are a substantial cause of NKX2-1-RDs. Diagnostic strategies should include this regulatory region and systematic structural variant detection, particularly when coding variants have been excluded. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- <i> <scp>NKX2</scp> ‐1 </i> Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea
- Date Crossref
- 16/07/2026
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Radboud University Nijmegen pays non établi dans la noticeUniversité ou école supérieure
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Radboud University Medical Center Department of Human Genetics Donders Institute for Brain pays non établi dans la noticeOrganisme public
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Netherlands Metabolomics Centre pays non établi dans la noticeStructure de recherche
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Hebron University pays non établi dans la noticeUniversité ou école supérieure
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Hospital Universitario Virgen del Rocío pays non établi dans la noticeÉtablissement de santé
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Radboud University Nijmegen, Department of Human Genetics Donders Institute for Brain — Radboud University Medical Center et Netherlands Metabolomics Centre, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.