EHMT1

Chr 9AD

euchromatic histone lysine methyltransferase 1

Also known as: EHMT1-IT1, EUHMTASE1, Eu-HMTase1, FP13812, GLP, GLP1, KLEFS1, KMT1D

NCBI Gene: 79813 ENSG00000181090 UniProt: Q9H9B1 OMIM: 607001

The encoded histone methyltransferase methylates lysine-9 of histone H3 to repress gene transcription and may regulate MYC- and E2F-responsive genes involved in cell cycle transition. Loss-of-function mutations cause Kleefstra syndrome 1, an autosomal dominant neurodevelopmental disorder. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— EHMT1

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Gene-Disease Validity (ClinGen)

Kleefstra syndrome · 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 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EHMT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 7.42

OE 0.02 (0.00–0.07)

Highly constrained

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

Missense Constraint?

1.16Z-score

OE missense 0.88 (0.83–0.94)

713 obs / 805.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.02 (0.00–0.07)

0≤0.351.4

Missense OE?0.88 (0.83–0.94)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 1 / 66.1Missense obs/exp: 713 / 805.9Syn Z: -3.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEHMT1-related Kleefstra syndromeLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.3392th %ile

LOF

0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.07

Literature Evidence

LOFSuch information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with EHMT1 haploinsufficiency.1

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

References