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

Background: O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the gene. The aim of this study was to investigate the role of 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 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 heterozygous splicing variant (c.1248+1G>T) in the gene. transcript analysis showed that the proband did not carry any mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G>T variant resulted in exon 12 skipping, which in turn caused an alteration in 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 c.1248+1G>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.