NKX2 ‐1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Movement Disorders
DOI: 10.1002/mds.70432
Authors: Robin Wijngaard, Lucy Dougherty‐de Miguel, German Demidov, Galuh Astuti, Amaia Lasa‐Aranzasti, Ana Cueto‐González, Marta Correa‐Vela, Carlos Lázaro‐Hernández, Charlotte A. Haaxma, Clara D.M. van Karnebeek, David Gómez‐Andrés, Ignacio Iglesias‐Serrano, Jiddeke M. van de Kamp, Jolanda Schieving, Laura Trujillano, Marc Engelen, Beatriz Muñoz‐Cabello, Roderick P.P.W.M. Maas, Thatjana Gardeitchik, Victoria Gonzalez, Annemarie de Vreugd, Cristina Pérez‐Sanchez, Elisabet Lloveras, Erik‐Jan Kamsteeg, Maartje Pennings, Natalia Rey‐Viñets, Javier Sánchez, Ronald van Beek, Antonio Moreno‐Galdó, Lisenka E.L.M. Vissers, Kornelia Neveling, Anna Marcé‐Grau, Machteld M. Oud, Belén Pérez‐Dueñas
Institutions: Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Universitat Autònoma de Barcelona, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, University of Tübingen, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Amsterdam UMC Location University of Amsterdam, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amalia Kinderziekenhuis, Centre for Biomedical Network Research on Rare Diseases, Universidad de Sevilla
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
OpenAlex ID: W7169505801