NKX2-1

Chr 14AD

NK2 homeobox 1

Also known as: BCH, BHC, NK-2, NKX2.1, NKX2A, NMTC1, T/EBP, TEBP

NCBI Gene: 7080 ENSG00000136352 UniProt: P43699

This gene encodes a transcription factor that binds to the thyroglobulin promoter to regulate thyroid-specific gene expression and also controls genes involved in morphogenesis. Mutations cause autosomal dominant conditions including benign hereditary chorea, choreoathetosis with congenital hypothyroidism and neonatal respiratory distress, and nonmedullary thyroid cancer. The pathogenic mechanism involves loss of function of this critical transcriptional regulator.

Summary from RefSeq, OMIM, UniProt, Mechanism

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Primary Disease Associations & Inheritance

{Thyroid cancer, nonmedullary, 1}MIM #188550

Chorea, hereditary benignMIM #118700

Choreoathetosis, hypothyroidism, and neonatal respiratory distressMIM #610978

UniProtChoreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction

Active trials

Pubs (1 yr)

210

P/LP submissions

16%

P/LP missense

0.59

LOEUF

LOF

Mechanism· G2P

Clinical Summary— NKX2-1

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Gene-Disease Validity (ClinGen)

NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

160 unique Pathogenic / Likely Pathogenic· 156 VUS of 441 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — NKX2-1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.59LOEUF

pLI 0.359

Z-score 2.61

OE 0.23 (0.10–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.81Z-score

OE missense 0.66 (0.58–0.76)

149 obs / 225.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.23 (0.10–0.59)

0≤0.351.4

Missense OE0.66 (0.58–0.76)

0≤0.61.4

Synonymous OE1.12

0≤1.21.6

LoF obs/exp: 3 / 13.2Missense obs/exp: 149 / 225.2Syn Z: -0.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNKX2-1-related choreoathetosis, hypothyroidism, and neonatal respiratory distressLOFAD

0.6646th %ile

GOF

0.3689th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 41% of P/LP variants are LoF

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMost NKX2-1 mutations are assumed to result in brain-lung-thyroid syndrome through haploinsufficiency, and only five NKX2-1 mutations with dominant-negative effects have been reported so far.PMID:29882472

LOFHaploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction.PMID:31707387

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.