KMT2E

Chr 7AD

lysine methyltransferase 2E (inactive)

Also known as: HDCMC04P, MLL5, NKp44L, ODLURO, SETD5B

NCBI Gene: 55904 ENSG00000005483 UniProt: Q8IZD2 OMIM: 608444

This gene encodes a chromatin-modifying enzyme that regulates gene transcription by binding to tri-methylated histone H3 and plays key roles in cell cycle progression and hematopoietic differentiation. Mutations cause O'Donnell-Luria-Rodan syndrome, a neurodevelopmental disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its critical biological importance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— KMT2E

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.06LOEUF

pLI 1.000

Z-score 8.11

OE 0.01 (0.00–0.06)

Highly constrained

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

Missense Constraint

1.42Z-score

OE missense 0.87 (0.82–0.92)

849 obs / 973.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.01 (0.00–0.06)

0≤0.351.4

Missense OE0.87 (0.82–0.92)

0≤0.61.4

Synonymous OE1.18

0≤1.21.6

LoF obs/exp: 1 / 78.6Missense obs/exp: 849 / 973.7Syn Z: -2.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKMT2E-related neurodevelopmental disorder/O'Donnell-Luria-Rodan syndromeLOFAD

0.16100th %ile

GOF

0.1899th %ile

LOF

0.92top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.06

Literature Evidence

LOFHaploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.PMID:31079897

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