Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
A homozygous EHMT2 splice donor variant c.328+2T>G was identified by exome sequencing in one unrelated adult female patient with intellectual disability, aggressive behavior, ventricular septal defect, supernumerary nipple, and umbilical hernia (PMID:39674972). The variant is absent from population databases and predicted to abolish the intron 3 splice donor site; RNA-seq confirmed the usage of cryptic donor sites leading to out-of-frame and in-frame transcript effects. Methylation profiling via the clinically validated EpiSign assay demonstrated the Kleefstra syndrome episignature, supporting a loss-of-function mechanism for EHMT2 (PMID:39674972). These findings implicate EHMT2 in an autosomal recessive neurodevelopmental disorder resembling Kleefstra syndrome with strong epigenetic concordance. Additional unrelated cases and functional validation studies are required to confirm this association. Key Take-home: EHMT2 loss-of-function variants define a novel autosomal recessive neurodevelopmental syndrome with diagnostic and research utility.
Gene–Disease AssociationLimitedSingle homozygous LoF variant with supporting epigenetic signature in one proband ([PMID:39674972]) Genetic EvidenceLimitedOne unrelated proband with homozygous splice donor LoF variant c.328+2T>G absent in population databases ([PMID:39674972]) Functional EvidenceModerateRNA-seq confirmed aberrant splicing and EpiSign assay demonstrated a Kleefstra syndrome episignature consistent with EHMT2 loss-of-function ([PMID:39674972]) |