NKX2-1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea.
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Wijngaard Robin, Dougherty-de Miguel Lucy, Demidov German, Astuti Galuh, Lasa-Aranzasti Amaia, Cueto-González Ana, Correa-Vela Marta, Lázaro-Hernández Carlos, Haaxma Charlotte A, van Karnebeek Clara D M, Gómez-Andrés David, Iglesias-Serrano Ignacio, van de Kamp Jiddeke M, Schieving Jolanda, Trujillano Laura, Engelen Marc, Muñoz-Cabello Beatriz, Maas Roderick P P W M, Gardeitchik Thatjana, Gonzalez Victoria, de Vreugd Annemarie, Pérez-Sanchez Cristina, Lloveras Elisabet, Kamsteeg Erik-Jan, Pennings Maartje, Rey-Viñets Natalia, Sánchez Javier, van Beek Ronald, Moreno-Galdó Antonio, Vissers Lisenka E L M, Neveling Kornelia, Marcé-Grau Anna, Oud Machteld M, Pérez-Dueñas Belén
Аннотация
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.