MSX1

Chr 4AD

msh homeobox 1

Also known as: ECTD3, HOX7, HYD1, STHAG1

NCBI Gene: 4487 ENSG00000163132 UniProt: P28360 OMIM: 142983

This gene encodes a transcriptional repressor that regulates embryonic development, particularly controlling odontogenesis (tooth development), craniofacial formation including palatal shelf fusion, and nail plate formation. Mutations cause autosomal dominant disorders affecting teeth and orofacial structures, including selective tooth agenesis with or without orofacial clefts, Witkop syndrome (ectodermal dysplasia with nail dysplasia and tooth abnormalities), and isolated orofacial clefts. These conditions typically present at birth or become apparent during early childhood as teeth develop.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.013 OMIM phenotypes

Clinical Summary— MSX1

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Gene-Disease Validity (ClinGen)

tooth agenesis, selective, 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.01LOEUF

pLI 0.165

Z-score 1.57

OE 0.32 (0.13–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.28Z-score

OE missense 0.94 (0.82–1.07)

158 obs / 168.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.13–1.01)

0≤0.351.4

Missense OE?0.94 (0.82–1.07)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 2 / 6.2Missense obs/exp: 158 / 168.1Syn Z: -1.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMSX1-related cleft lip with or without cleft palateLOFAD

This gene — mechanism propensity

0.6550th %ile

GOF

0.3788th %ile

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

DNWe propose that the Arg31Pro missense mutation produces the phenotype of FTA via a dominant negative mechanism. Because this homeoprotein is expected to interact with other transcription factors 18Â·21 and binds DNA 18, Arg31Pro MSXI could functionally inactivate partner proteins as well as perturb 1

LOFA nonsense mutation in MSX1 causes Witkop syndrome2

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

References