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Brain-lung-thyroid syndrome is an autosomal dominant multisystem disorder caused by heterozygous variants in NKX2-1, characterized by benign chorea, neonatal respiratory distress, and congenital hypothyroidism. Patients often present in infancy with hypotonia and motor delay, followed by choreoathetosis, variable pulmonary disease, and thyroid dysfunction. Recognition of this triad avoids misdiagnosis as ataxic cerebral palsy or isolated endocrine or pulmonary conditions. Clinical penetrance of movement disorders approaches 100%, whereas thyroid and lung involvement show variable expressivity.
Genetic evidence is robust: 101 index patients harbored 17 point mutations and 10 deletions in NKX2-1 (101 probands PMID:24714694). Variant classes include missense within the homeodomain, nonsense, frameshift, intragenic deletions, and regulatory deletions. A de novo missense variant c.632A>G (p.Lys211Arg) abolishes DNA binding across target promoters (p.Lys211Arg) PMID:38757609. Familial segregation identified 6 affected relatives in a three-generation pedigree (6 relatives) PMID:29621620 and a father–daughter pair (2 relatives) PMID:30186310.
Segregation data across multiple families support a fully penetrant neurologic phenotype, with 8 additional affected relatives carrying pathogenic NKX2-1 variants. Thyroid hormone deficiency and pulmonary disease show incomplete penetrance and variable expressivity, warranting comprehensive genetic testing including sequencing and dosage analysis.
Functional assays confirm a haploinsufficiency mechanism. The p.Arg165GlyfsTer32 mutant lacks DNA binding and fails to transactivate thyroglobulin and surfactant protein promoters, exerting a dominant-negative effect on the Tg promoter PMID:23379327. Ttf1(+/−) mice display gait abnormalities and mild hyperthyrotropinemia, mirroring human neurologic and thyroid defects PMID:11854318. Coexpression of TAZ/WWTR1 rescues lung promoter activity of carboxy-terminal but not amino-terminal mutants, highlighting modifier effects on the pulmonary phenotype PMID:29294041.
Additional evidence implicates deletions of MBIP adjacent to NKX2-1 that reduce NKX2-1 transcript levels and mimic haploinsufficiency in fibroblasts PMID:29621620. No recurrent founder alleles have been reported. Population studies confirm the rarity of NKX2-1 variants in isolated congenital hypothyroidism or interstitial lung disease cohorts without neurologic signs.
Integration of clinical, genetic, and experimental data establishes a Definitive gene-disease association. NKX2-1 testing guides diagnosis, informs endocrine and respiratory management, and enables genetic counselling. Early molecular diagnosis is critical for surveillance and treatment of neurologic, pulmonary, and thyroid manifestations. Key Take-home: Heterozygous NKX2-1 variants definitively cause brain-lung-thyroid syndrome, supporting comprehensive screening in affected infants.
Gene–Disease AssociationDefinitive101 index patients, multi-family segregation (8 affected relatives), concordant functional studies Genetic EvidenceStrong17 point mutations and 10 deletions in 101 index patients; reached genetic evidence cap Functional EvidenceStrongMouse heterozygous model, in vitro transactivation and rescue assays confirm haploinsufficiency |