EHMT1 – Kleefstra syndrome

EHMT1 (euchromatic histone‐lysine N‐methyltransferase 1) haploinsufficiency is the molecular basis of Kleefstra syndrome, a rare autosomal dominant neurodevelopmental disorder. Patients present with intellectual disability, childhood hypotonia, characteristic facial features, congenital heart defects, seizures and behavioral anomalies. Diagnostic testing includes chromosomal microarray to detect 9q34.3 deletions encompassing EHMT1 or targeted sequencing to identify intragenic loss‐of‐function variants.

Genetic evidence for the association is robust: comprehensive sequencing of EHMT1 in 209 individuals with suspected Kleefstra syndrome identified heterozygous de novo nonsense, frameshift, splice‐site and critical missense variants in 191 cases, confirming haploinsufficiency as the disease mechanism (209 probands) [PMID:39013458]. Early studies described three de novo loss‐of‐function mutations (nonsense and frameshift) and microdeletions spanning EHMT1 in 23 patients, definitively establishing causality [PMID:16826528]. Variants segregate with disease in multiple unrelated families, with no unaffected carriers.

Functional assays support a haploinsufficiency mechanism: patient fibroblasts carrying a de novo frameshift deletion show markedly reduced H3K9 dimethylation, reflecting loss of EHMT1 methyltransferase activity [PMID:28361100]. Induced pluripotent stem cell–derived cortical neurons from EHMT1‐deficient patients exhibit decreased synchronicity of network bursts and altered synaptic firing patterns, linking epigenetic dysregulation to neuronal dysfunction [PMID:27767173].

Additional functional genomics using comprehensive variant analysis revealed distinct domain‐specific effects: ankyrin‐repeat “reader” variants produce a mild Kleefstra syndrome DNA methylation signature, whereas SET‐domain “writer” mutations lack this signature despite causing typical clinical features, underscoring the utility of epigenomic profiling in variant interpretation [PMID:39013458].

No conflicting evidence has been reported; genotype–phenotype correlations remain consistent across microdeletion and intragenic mutation cohorts. The high penetrance of de novo LoF variants and concordant functional data over nearly two decades support a Definitive ClinGen classification.

Key take-home: EHMT1 haploinsufficiency causes Kleefstra syndrome via loss of H3K9 methylation, justifying routine deletion/sequence screening of EHMT1 in patients with characteristic neurodevelopmental and congenital features.

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