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. 2022 Jan;10(1):e1840.
doi: 10.1002/mgg3.1840. Epub 2021 Oct 28.

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

Niall Patrick Keegan  1   2   3 , Sue Fletcher  1   2   4
Affiliations

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

Niall Patrick Keegan et al. Mol Genet Genomic Med. 2022 Jan.

Abstract

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.

Keywords: RNA splicing; cryptic exon; genome-wide association study; single-nucleotide polymorphism.

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Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
A general model of SNPtic exon splicing. A cryptic exon, or CE (dashed‐line box) is included in mature transcripts at frequencies that vary depending on the genotype of the carrier. Because the CE encodes a premature stop codon more than 55 nt from the final splice junction, mature transcripts that include the CE are targeted for nonsense‐mediated decay (NMD, grey circle) and are not translated. If a patient carries an SNV (C>G) that greatly increases CE inclusion, NMD predominates and little protein is translated, resulting in a rare but distinct disease phenotype. Conversely, through similar mechanisms a common SNP (A>T) with a weak effect on CE splicing leads to a common but indistinct phenotype, which may only be measurable with a sufficiently powered genome‐wide association study
FIGURE 2
FIGURE 2
Cryptic exons APC‐11a, LHCGR‐6a and POC1B‐9a exhibit high sequence conservation. Images were captured as screenshots from the UCSC Genome Browser (Kent et al., 2002). In descending order, displayed tracks are: Base position, dbSNP 153, input sequence, ‘GENCODE V37’ (aligned transcript variants) and ‘Cons 30 Primates’. ‘The Cons 30 Primates’ track, which is erroneously labelled as ‘Cons 30 Mammals’ in the browser, displays sequence conservation data from 30 non‐human primate species
See this image and copyright information in PMC

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