EHMT2 is a candidate gene associated with a neurodevelopmental disorder (NDD) showing Kleefstra-like phenotype. To date, only two patients with variants in this gene have been reported, suggesting distinct Mendelian inheritance patterns:
● One case with autosomal recessive inheritance, involving a homozygous splice site variant and a DNA methylation episignature overlapping that of Kleefstra syndrome 1 (KS1, caused by pathogenic EHMT1 variants);
● One case with a dominant pattern of inheritance, involving a de novo missense variant in the SET domain of the protein, associated with reduced enzymatic activity and a partially overlapping KS1 episignature.
Clinical features shared by both patients include:
• Global developmental delay
• Intellectual disability
• Hypotonia
• Subtle facial dysmorphisms
The prevalence of deleterious EHMT2 variants in NDD cases remains unknown. There is a small number of cases and lacks scientific literature derived from functional assays that would provide a mechanistic link between EHMT2 deleterious variants and an NDD phenotype. Therefore, this gene has not yet been definitively confirmed as causative of NDDs, and further patient reports and functional studies are needed.
EHMT2 encodes a histone methyltransferase that acts in partnership with EHMT1 to catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9me1/2). This epigenetic modification plays a critical role in gene repression impacting development, cellular differentiation, and synaptic plasticity, being particularly relevant to neurodevelopmental processes.
EHMT2