<i> <scp>NKX2</scp> ‐1 </i> Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea

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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Journal
Movement Disorders
Published
2026-07-16
DOI
https://doi.org/10.1002/mds.70432
Primary Topic
Genomics and Rare Diseases
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article
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article

NKX2 ‐1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea

Beatriz Muñoz Cabello, Kornelia Neveling, German Demidov, Marta Correa‐Vela et al.
Movement Disorders
Genomics and Rare Diseases
article

NKX2 ‐1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea

Beatriz Muñoz Cabello, Kornelia Neveling, German Demidov, Marta Correa‐Vela, Laura Trujillano, Machteld M. Oud, Charlotte A. Haaxma, Belén Pérez‐Dueñas, Thatjana Gardeitchik, Ronald van Beek, Robin Wijngaard, Lisenka E.L.M. Vissers, Antonio Moreno, Anna M. Cueto‐González, Lucía Dougherty‐de Miguel, David Gómez‐Andrés, Amaia Lasa‐Aranzasti, Galuh Astuti, Marc Engelen, Anna Marcé‐Grau, Roderick P.P.W.M. Maas, Ignacio Iglesias Serrano, Victoria González, Maartje Pennings, Erik‐Jan Kamsteeg, A. de Vreugd, Clara D.M. van Karnebeek, Cristina Pérez-Sánchez, Elisabet Lloveras, Carlos Lazaro-Hernandez, Javier Sánchez, Natalia Rey‐Viñets, Jiddeke M. van de Kamp, Jolanda Schieving
article en

Abstract

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.

Movement Disorders
Hebron University (PS), Universitat Autònoma de Barcelona (ES), Synlab Czech (Czechia) (CZ), Radboud University Nijmegen (NL), Radboud University Medical Center (NL), Netherlands Metabolomics Centre (NL), Vall d'Hebron Institut de Recerca (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Amalia Kinderziekenhuis (NL), Vall d'Hebron Hospital Universitari (ES), Instituto de Biomedicina de Sevilla (ES), Eurofins (Denmark) (DK), Amsterdam University Medical Centers (NL), Hospital Universitario Virgen del Rocío (ES), University of Tübingen (DE), University of Amsterdam (NL), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Partnerships for the goals
Openalex Percentile: Top 8%
Genomics and Rare Diseases
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