NFIX

Chr 19AD

nuclear factor I X

Also known as: CTF, MALNS, MRSHSS, NF-I/X, NF1-X, NF1A, SOTOS2

NCBI Gene: 4784 ENSG00000008441 UniProt: Q14938 OMIM: 164005

This transcription factor binds to specific palindromic DNA sequences in viral and cellular promoters to regulate gene expression. Loss-of-function mutations cause Malan syndrome and Marshall-Smith syndrome through autosomal dominant inheritance. The protein is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3 in viral and cellular promoters. The encoded protein can also stimulate adenovirus replication in vitro. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.152 OMIM phenotypes

Clinical Summary— NFIX

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Gene-Disease Validity (ClinGen)

Marshall-Smith syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 0.999

Z-score 4.15

OE 0.00 (0.00–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.08Z-score

OE missense 0.29 (0.24–0.36)

78 obs / 264.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.15)

0≤0.351.4

Missense OE?0.29 (0.24–0.36)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 0 / 20.1Missense obs/exp: 78 / 264.8Syn Z: 0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNFIX-related Marshall-Smith syndromeLOFAD

This gene — mechanism propensity

0.4389th %ile

GOF

0.3887th %ile

LOF

0.84top 5%

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 · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNThe exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome.1

LOFWhereas the overgrowth phenotype is due to NFIX haploinsufficiency, the presence of both normal and mutated alleles in MSS supports that mutated RNAs escape NMD surveillance.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