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

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

Published in

Movement disorders : official journal of the Movement Disorder Society. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

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.
The objective of this study was to evaluate the clinical spectrum and frequency of regulatory variants in NKX2-1-RDs.
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.
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.
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.

PMID:
42464514
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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