EHMT1 – Kleefstra Syndrome 1

Kleefstra syndrome 1 (KS1) is a rare autosomal dominant neurodevelopmental disorder characterized by intellectual disability, childhood hypotonia, characteristic facial dysmorphisms, and often autistic features. KS1 is caused by haploinsufficiency of the EHMT1 gene due to heterozygous loss‐of‐function variants or microdeletions in 9q34.3, resulting in reduced histone H3 lysine 9 methylation and altered transcriptional repression (PMID:23232695).

Initial reports included a de novo 320-kb deletion encompassing EHMT1 in a 7-year-old girl with Tourette-like tics, intellectual disability, hypotonia, ADHD, OCD and self-injurious behavior (PMID:37817104). Subsequent studies described two additional de novo events: a frameshift p.Val692GlyfsTer64 and an 11 kb microdeletion of exons 19–25 (PMID:40428343), as well as a maternal mosaic splice donor mutation c.2712+1G>A leading to aberrant transcripts in the proband (PMID:23232695).

Larger cohorts have expanded the variant spectrum. Ten unrelated Chinese patients harbored three missense (p.Glu235Gly, p.Asp903Gly, p.Leu943Pro), three frameshifting, one nonsense (p.Arg246Ter), one splice (c.3540+2T>C) and one 9q34.3 deletion in EHMT1 (PMID:34265435). A comprehensive analysis of 209 individuals with rare EHMT1 variants confirmed pathogenic classification via DNA methylation signature profiling (PMID:39013458).

The EHMT1 variant spectrum includes truncating (nonsense/frameshift), splice-site, missense in the ankyrin repeat and SET domains, and microdeletions. Recurrent missense c.2426C>T (p.Pro809Leu) has been identified in multiple unrelated KS1 cases and shown to impair protein folding and histone‐mark binding (PMID:28057753).

Mechanistically, EHMT1 haploinsufficiency reduces H3K9me1/2 and disrupts neuronal network maturation. EHMT1-deficient neuronal cultures exhibit impaired synchronized bursting and excitatory synaptic activity (PMID:27767173); patient fibroblasts show decreased H3K9me2 levels (PMID:28361100); and CRISPR introduction of EHMT1 truncating variants in iPSCs recapitulates transcriptional and differentiation defects (PMID:35139903).

Collectively, strong genetic and experimental concordance over >15 years establishes EHMT1 loss‐of‐function as the definitive cause of KS1. Diagnostic screening for EHMT1 point mutations and 9q34.3 deletions is essential for early clinical management, genetic counseling, and exploration of epigenetic therapies.

References

• BMC neurology • 2023 • Tourette-like syndrome secondary to Kleefstra syndrome 1 with a de novo microdeletion in the EHMT1 gene. PMID:37817104
• Genes • 2025 • A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review. PMID:40428343
• European journal of human genetics • 2013 • A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. PMID:23232695
• European journal of medical genetics • 2021 • Clinical phenotypes and molecular findings in ten Chinese patients with Kleefstra Syndrome Type 1 due to EHMT1 defects. PMID:34265435
• American journal of human genetics • 2024 • Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome. PMID:39013458
• Scientific reports • 2016 • Euchromatin histone methyltransferase 1 regulates cortical neuronal network development. PMID:27767173
• Molecular genetics & genomic medicine • 2017 • A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation. PMID:28361100
• The Journal of biological chemistry • 2017 • A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. PMID:28057753
• Stem cell research & therapy • 2022 • CRISPR single base editing, neuronal disease modelling and functional genomics for genetic variant analysis: pipeline validation using Kleefstra syndrome EHMT1 haploinsufficiency. PMID:35139903

Evidence Based Scoring (AI generated)