The EHMT2 gene, located at 6p21.33, encodes a histone methyltransferase involved in mono- and dimethylation of histone H3 at lysine 9 (H3K9me1/2). The protein acts in cooperation with EHMT1 as part of an epigenetic complex responsible for tissue- and time-specific gene repression.
To date, two rare variants have been reported in association with Kleefstra-like neurodevelopmental phenotypes:
● A homozygous splice site variant (NM_006709.5): c.328+2T>G → RNA sequencing analysis revealed the activation of two cryptic donor splice sites within exon 3: one predicted to result in an in-frame alteration, and the other in an out-of-frame transcript. The authors hypothed that this variant generates a hypomorphic EHMT2 allele, leading to a marked reduction in fully functional EHMT2 protein levels and consequently impairing the activity of the EHMT1/2 epigenetic complex.
● A heterozygous missense variant in the SET domain p.Ala1077Ser, the catalytic region responsible for methyltransferase activity, potentially acting through dominant-negative effect or haploinsufficiency. The SET domain is the catalytic region responsible for histone methyltransferase activity.
In the homozygous case, the DNA methylation profile (episignature) was identical to that of Kleefstra syndrome 1 (EHMT1-related). In the heterozygous case, the episignature was similar, and a 3-5 fold reduction in the EHMT2 enzymatic activity was observed.
The pathophysiologic mechanism related to EHMT2damaging variants are under investigation.
Variant interpretation should be supported by clinical, functional, and epigenetic data. Recommended diagnostic tools include next-generation sequencing (NGS).
EHMT2