A Leaky Deep Intronic Splice Variant in Is Associated with Non-Syndromic Retinitis Pigmentosa.

BACKGROUND

Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis.

METHODS

Whole exome sequencing results were analyzed using established pipelines and the results were further confirmed by Sanger sequencing and minigene splicing assay.

RESULTS

Exome sequencing in a 51-year-old Ashkenazi Jewish patient with non-syndromic retinitis pigmentosa (RP) identified compound heterozygous variants in the gene: a known pathogenic missense [p.(N48K)] and a novel deep intronic variant c.254-643G>T. A minigene splicing assay that was performed aiming to study the effect of the c.254-643G>T variant on pre-mRNA splicing revealed the inclusion of a pseudo-exon that was also reported to be included in the transcript due to an adjacent variant, c.254-649T>G. However, unlike the reported c.254-649T>G variant, c.254-643G>T showed aberrant splicing in a leaky manner, implying that the identified variant is not totally penetrant.

CONCLUSION

We report on a novel deep intronic variant in causing non-syndromic RP. The non-syndromic phenotype observed in this index case may be attributed to the leaky nature of this variant, which is causing some normal transcripts to be produced.