Year: 2026
Type: article
Study design: Case Report
Abstract: Background 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. Methods 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. Results 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. Conclusion Our findings support a role for EHMT2 in an autosomal recessive neurodevelopmental disorder and allowed anticipatory guidance for the patient’s family.
Source: Frontiers in Genetics
Authors: Dmitrijs Rots, Beatriz Cristina de Oliveira, Laura Machado Lara Carvalho, Xiaonan Zhao, Bekim Sadikovic, Teresa Sim, Robert Rigobello, Matthew Tedder, Sarah Donoghue, Devi Priyanka Maripuri, Ales Hnizda, Eileen Barr, Robin Fletcher, Lenka Noskova, Dong Li, Tjitske Kleefstra, Elaine H. Zackai, Maria J. Barrero, Ana Cristina Victorino Krepischi, Alanna Strong
Institutions: Erasmus MC, Universidade de São Paulo, Consejo Superior de Investigaciones Científicas, Instituto Cajal, Baylor College of Medicine, Baylor Genetics, Western University, London Health Sciences Centre, Greenwood Genetic Center, Children's Hospital of Philadelphia, Charles University, General University Hospital in Prague, University of Pennsylvania, Radboud University Medical Center, Instituto de Salud Carlos III, Instituto de Investigación de Enfermedades Raras
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7166156381