A role for EHMT2 in a novel autosomal recessive neurodevelopmental syndrome? A case report

EHMT1 and EHMT2 encode histone methyltransferases that form an epigenetic complex mediating mono- and dimethylation of histone H3 at lysine 9 (H3K9me1/2). This complex modulates fundamental biological processes during embryonic and post-natal development. While EHMT1 has an established role in neurodevelopmental disease, with heterozygous pathogenic variants causing Kleefstra syndrome type 1 (KS1), the contribution of EHMT2 to neurodevelopmental disorders remains to be established. To date, seven probands harboring de novo heterozygous EHMT2 variants and one individual with a homozygous splice variant have been reported, all presenting with phenotypes and DNA methylation episignatures overlapping with KS1.

A male proband was referred for Genetics evaluation due to global developmental delay, autism spectrum disorder, hypotonia, dysmorphisms, posterior fossa malformation, congenital heart disease, umbilical hernia, and genitourinary anomalies. Trio genome sequencing identified compound heterozygous variants in EHMT2 (NM_006709.5:c.2648_2649del; p.(Glu883Glyfs*48), paternally inherited; NM_006709.5:c.2344-19_2344-16del; r.spl, maternally inherited). DNA methylation episignature profiling and RNA-sequencing were performed to assess the molecular consequences of these EHMT2 variants.

Proband phenotype strongly overlapped with that of KS1 and previously reported individuals with autosomal dominant and recessive EHMT2-related neurodevelopmental disorder. DNA methylation episignature was consistent with KS1. Transcripts bearing the paternally inherited EHMT2 frameshift variant were under-represented in the RNA-sequencing data, likely reflecting partial nonsense-mediated decay. The maternally inherited EHMT2 variant causes multiple aberrant splicing events in a subset of transcripts (∼25%), including retention of 291 nucleotides from intron 18, which generates a nonsense variant in the canonical EHMT2 transcript.

Our findings support a role for EHMT2 in an autosomal recessive neurodevelopmental disorder and allowed anticipatory guidance for the patient's family.