{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T15:47:05Z","timestamp":1793029625269,"version":"4.5.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>EHMT1<\/jats:italic>\n                      and\n                      <jats:italic>EHMT2<\/jats:italic>\n                      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\n                      <jats:italic>EHMT1<\/jats:italic>\n                      has an established role in neurodevelopmental disease, with heterozygous pathogenic variants causing Kleefstra syndrome type 1 (KS1), the contribution of\n                      <jats:italic>EHMT2<\/jats:italic>\n                      to neurodevelopmental disorders remains to be established. To date, seven probands harboring\n                      <jats:italic>de novo<\/jats:italic>\n                      heterozygous\n                      <jats:italic>EHMT2<\/jats:italic>\n                      variants and one individual with a homozygous splice variant have been reported, all presenting with phenotypes and DNA methylation episignatures overlapping with KS1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>EHMT2<\/jats:italic>\n                      (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\n                      <jats:italic>EHMT2<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Proband phenotype strongly overlapped with that of KS1 and previously reported individuals with autosomal dominant and recessive\n                      <jats:italic>EHMT2<\/jats:italic>\n                      -related neurodevelopmental disorder. DNA methylation episignature was consistent with KS1. Transcripts bearing the paternally inherited\n                      <jats:italic>EHMT2<\/jats:italic>\n                      frameshift variant were under-represented in the RNA-sequencing data, likely reflecting partial nonsense-mediated decay. The maternally inherited\n                      <jats:italic>EHMT2<\/jats:italic>\n                      variant causes multiple aberrant splicing events in a subset of transcripts (\u223c25%), including retention of 291 nucleotides from intron 18, which generates a nonsense variant in the canonical\n                      <jats:italic>EHMT2<\/jats:italic>\n                      transcript.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings support a role for\n                      <jats:italic>EHMT2<\/jats:italic>\n                      in an autosomal recessive neurodevelopmental disorder and allowed anticipatory guidance for the patient\u2019s family.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1824138","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:45:53Z","timestamp":1782452753000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A role for EHMT2 in a novel autosomal recessive neurodevelopmental syndrome? 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