NKX2-1

Chr 14

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.59

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

136 unique Pathogenic / Likely Pathogenic· 153 VUS of 412 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NKX2-1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.23 (0.10–0.59)

0≤0.351.4

Missense OE?0.66 (0.58–0.76)

0≤0.61.4

Synonymous OE?1.12

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

This gene — mechanism propensity

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 · 74% 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.1

LOFHaploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction.2

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

References

ClinVar Variant Classifications

412 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic72

Likely Pathogenic64

VUS153

Likely Benign83

Benign18

Conflicting16

Pathogenic

Likely Pathogenic

153

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	61	6	5	0	72
Likely Pathogenic	40	23	1	0	64
VUS	4	126	15	8	153
Likely Benign	0	7	19	57	83
Benign	0	1	15	2	18
Conflicting	—				16
Total	105	163	55	67	406

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap NKX2-1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →