A Homozygous FOXA1 Variant Links Choreoathetosis, Bronchiectasis, and Anorectal–Axial Anomalies

BACKGROUND: FOXA1 encodes a forkhead-box pioneer transcription factor involved in chromatin accessibility, epithelial and endodermal lineage specification, pulmonary epithelial differentiation, and selected neurodevelopmental programs. Although somatic FOXA1 alterations are well recognized in cancer, a germline FOXA1-associated Mendelian disorder has not been defined. OBJECTIVES: To delineate the clinical and genetic features of a syndromic neuropulmonary phenotype associated with a homozygous FOXA1 variant. METHODS: We evaluated three affected individuals from an extended consanguineous Turkish family with childhood-onset action-induced hyperkinetic/choreoathetoid movement disorder, bronchiectatic lung disease, anorectal abnormalities, axial skeletal defects, and neurobehavioral features. Whole-exome sequencing with copy-number variant analysis, homozygosity mapping, and segregation analysis were performed. RESULTS: Exome-based analysis did not identify diagnostic variants in known disease genes relevant to the combined neurological, pulmonary, gastrointestinal, and skeletal phenotype. Homozygosity mapping identified a 16.8-Mb shared homozygous interval on chromosome 14 encompassing FOXA1. All three affected individuals carried the same homozygous FOXA1 c.623G>C, p.(Arg208Pro) variant, which segregated with the phenotype under an autosomal recessive model. The variant affects a conserved residue within the DNA-binding forkhead domain and was absent in the homozygous state from population databases. The clinical pattern partially overlaps with NKX2-1-related brain-lung disease but appears distinct, with preserved thyroid function and prominent bronchiectatic airway, anorectal, and axial skeletal involvement. CONCLUSION: These findings support FOXA1 as a plausible candidate disease gene for an emerging autosomal recessive syndromic neuropulmonary disorder with anorectal and axial skeletal involvement.