NKX2-5

Chr 5AD

NK2 homeobox 5

Also known as: CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3

NCBI Gene: 1482 ENSG00000183072 UniProt: P52952 OMIM: 600584

This gene encodes a homeobox transcription factor required for heart and spleen development that binds to specific DNA motifs and cooperates with other transcription factors like GATA4. Mutations cause various congenital heart malformations including atrial septal defects, tetralogy of Fallot, hypoplastic left heart syndrome, and ventricular septal defects, as well as congenital nongoitrous hypothyroidism. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants (pLI 0.95).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.336 OMIM phenotypes

Clinical Summary— NKX2-5

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Gene-Disease Validity (ClinGen)

NKX2.5-related congenital, conduction and myopathic heart disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.945

Z-score 2.81

OE 0.00 (0.00–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

0.20Z-score

OE missense 0.96 (0.85–1.09)

178 obs / 185.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.33)

0≤0.351.4

Missense OE0.96 (0.85–1.09)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 0 / 9.2Missense obs/exp: 178 / 185.6Syn Z: -0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNKX2-5-related dilated cardiomyopathyOTHERAD

definitiveNKX2-5-related congenital hypothyroidism non-goitrousDNAD

definitiveNKX2-5-related tetralogy of FallotOTHERAD

definitiveNKX2-5-related atrial septal defect with atrioventricular conduction defectsLOFAD

0.4586th %ile

GOF

0.2696th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). 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 · LOEUF 0.33

DN1 literature citation

GOF1 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

DNNKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominPMID:16418214

GOFOur study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.PMID:26146939

LOFTwo are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding.PMID:9651244

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