Laia Nou‐Fontanet, Claudia Ravelli, Lydie Bürglen, Sol Balsells Mejia, Angel Valls‐Villalba, Elies Roman Schiffels, Alice Innocenti, Beatriz Villafuerte, Ainara Salazar‐Villacorta, Vicente Quiroz, Andrea Sariego Jamardo, Giulia Bonato, Asun Díaz‐Gomez, A. Afenjar, Catheline Vilain, Patricia Dumke da Silva Moller, Deyanira Garcia‐Navas Nuñez, Magdalena Krygier, Mária Judit Molnár, Łukasz Milanowski, K. Õunap, Micaela Pauni, Patricia Vega, Raphael Borie, Milena Villamil‐Osorio, Sanem Yilmaz, Dénes Zádori, Marta Zawadzka, Tahsin Stefan Barakat, Sebastian Neuens, Daniel de Natera‐de Benito, Dídac Casas‐Alba, Luca Soliani, Claudio Melo de Gusmão, Giacomo Garone, Nicola Specchio, Miryam Carecchio, J. A. Moreno, Francesca Magrinelli, Kailash P. Bhatia, Darius Ebrahimi‐Fakhari, C. Castiglioni, Manju Ann Kurian, João Nuno Carvalho, Roser Pons, Emmanuel Flamand Roze, Diane Doummar, Juan Darío Ortigoza‐Escobar
BACKGROUND: NKX2-1-related disorders result from heterozygous variants in NKX2-1, a gene crucial for brain, lung, and thyroid development. Although movement disorders, hypothyroidism, and neonatal respiratory distress are recognized, the full phenotype and genotype-phenotype relationships remain incompletely defined. OBJECTIVES: To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories - particularly chorea - and explore genotype-phenotype associations with clinical relevance. METHODS: We conducted a multicenter, cross-sectional study recruiting participants through referral clinicians and European networks. Standardized clinical and genetic data were captured in an electronic database and analyzed with descriptive and inferential statistics. RESULTS: Sixty-eight individuals (37 female; median age 16 years, range 2-60 years) were included. Motor delay was the commonest presenting feature (~60%); neonatal respiratory distress syndrome occurred in one-third of cases. The brain-lung-thyroid triad was present in almost half. Chorea affected over 90% and began in early childhood; it was more frequent with single nucleotide variants than with deletions. Deletions are associated with better gross motor function. Frameshift or nonsense variants showed greater respiratory involvement, and variants in the exon-3 homeobox region were associated with age-related reduction of chorea. Neonatal respiratory distress predicted later respiratory symptoms. Greater abnormal involuntary movement severity correlated with poorer manual and gross motor function. Hypotonia and untreated hypothyroidism are associated with more severe chorea. Psychiatric comorbidity occurred in over one-third of cases, mainly attention-deficit/hyperactivity symptoms. CONCLUSIONS: This largest cohort to date shows early neurological onset, genotype-specific outcomes, and frequent psychiatric comorbidity in NKX2-1-related disorders, refining clinical expectations and supporting genotype-informed diagnosis, counseling, and management. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.