A spotter's guide to SNPtic exons: The common splice variants underlying some SNP-phenotype correlations

Cryptic exons are typically characterised as deleterious splicing aberrations caused by deep intronic mutations. However, low-level splicing of cryptic exons is sometimes observed in the absence of any pathogenic mutation. Five recent reports have described how low-level splicing of cryptic exons can be modulated by common single-nucleotide polymorphisms (SNPs), resulting in phenotypic differences amongst different genotypes.

We sought to investigate whether additional 'SNPtic' exons may exist, and whether these could provide an explanatory mechanism for some of the genotype-phenotype correlations revealed by genome-wide association studies. We thoroughly searched the literature for reported cryptic exons, cross-referenced their genomic coordinates against the dbSNP database of common SNPs, then screened out SNPs with no reported phenotype associations.

This method discovered five probable SNPtic exons in the genes APC, FGB, GHRL, MYPBC3 and OTC. For four of these five exons, we observed that the phenotype associated with the SNP was compatible with the predicted splicing effect of the nucleotide change, whilst the fifth (in GHRL) likely had a more complex splice-switching effect.

Application of our search methods could augment the knowledge value of future cryptic exon reports and aid in generating better hypotheses for genome-wide association studies.