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Background  O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the  KMT2E  gene. The aim of this study was to investigate the role of  KMT2E  mutations as a cause of ODLURO syndrome in a Chinese boy.    Methods  We reported the clinical course of a Chinese boy who was diagnosed with ODLURO syndrome by the whole exome sequencing. We extracted genomic DNA of the proband and parents, gene variations were screened using whole-exome sequencing, followed by validation using direct Sanger sequencing. The effect of mRNA splicing variants were analyzed through a minigene splice assay and  in vitro  reverse transcription PCR (RT-PCR).    Results  The proband presented with recurrent seizures and developmental delay. Using genetic analysis, we identified that the proband carried a  de novo  heterozygous splicing variant (c.1248+1G&amp;gt;T) in the  KMT2E  gene.  In vivo  transcript analysis showed that the proband did not carry any  KMT2E  mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The  in vitro  minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G&amp;gt;T variant resulted in exon 12 skipping, which in turn caused an alteration in  KMT2E  mRNA splicing. The mutant transcript created a premature stop codon at the 378 amino acid position that could have been caused nonsense-mediated mRNA decay (NMD).    Conclusion  We verified the pathogenic effect of the  KMT2E  c.1248+1G&amp;gt;T splicing variant, which disturbed normal mRNA splicing and caused mRNA decay. Our findings suggest that splice variants play an important role in the molecular basis of ODLURO, and that careful molecular profiling of these patients could play an essential role in tailoring of personalized treatment options soon.

Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient