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

• Published in: Molecular genetics & genomic medicine Vol. 10; no. 1; pp. e1840 - n/a
• Main Authors: Keegan, Niall Patrick, Fletcher, Sue
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2022; John Wiley and Sons Inc; Wiley
• Subjects: Alternative splicing; cryptic exon; Exons; Gene expression; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype & phenotype; Genotypes; Humans; Introns; Method; Mutation; Nucleotides; Pathogenesis; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; RNA splicing; Single-nucleotide polymorphism; Splicing; cryptic exon; single-nucleotide polymorphism; genome-wide association study; RNA splicing
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1840

Background 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. Methods 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. Results 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. Conclusion 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. Some mutations cause high levels of cryptic exon inclusion in transcripts of the mutated gene, disrupting their coding sequence and resulting in a disease phenotype. Through similar mechanisms, common polymorphisms (SNPs) can cause sub‐clinical variations in cryptic exon splicing, which may be detectable as SNP‐linked population phenotypes.