Table 1.
Overview of experimental studies on the prevalence of exonic splice information
| References | Exon (size) | Variants tested | Proportion of splice-associated sites | Proportion of splice-disrupting variants | Definition of splice alteration | Examples of diseases associated to gene |
|---|---|---|---|---|---|---|
| Pagani et al. (2003) | CFTR exon 9 (183 bp) | Variants previously reported in patients and artificial variants | 21/29 (~72.4%) (includes some indels and multiple mutations) | 32/47 (~68.1%) (includes some indels and multiple mutations) | Undefined | Cystic fibrosis (Cheng et al. 1990) |
| Pagani et al. (2005) | CFTR exon 12 (87 bp) | Most possible synonymous single base substitutions between positions 13 and 52 in the exon | 5/12 (~41.7%) | 6/19 (~31.6%) | Undefined | See above |
| Tournier et al. (2008) | MLH1 and MSH2 (various exons) | Variants (of unknown significance or deleterious) from Lynch syndrome families | 13/67 (~19.4%) (includes short indels) | 13/67 (~19.4%) (includes short indels) | Determined using a t test (distribution from 3 replicate experiments) | Lynch syndrome (Bonadona et al. 2011; Fishel et al. 1993; Bronner et al. 1994) |
| Thery et al. (2011) | BRCA1 and BRCA2 (various exons) | Variants of unknown significance from families undergoing genetic counselling | 6/30 (20.0%) | 6/30 (20.0%) | Undefined | Breast cancer (Antoniou et al. 2003; Easton et al. 1993; Wooster et al. 1995), ovarian cancer (Antoniou et al. 2003), Fanconi anemia (Howlett et al. 2002) |
| Gaildrat et al. (2012) | BRCA2 exon 7 (115 bp) | Variants of unknown significance from families undergoing genetic counselling | 6/8 (75.0%) | 6/8 (75.0%) | Undefined | Breast cancer (Antoniou et al. 2003; Wooster et al. 1995), ovarian cancer (Antoniou et al. 2003), Fanconi anemia (Howlett et al. 2002) |
| Di Giacomo et al. (2013) | BRCA2 exon 7 (115 bp) | Variants reported in breast and ovarian cancer patients | 7/23 (~30.4%) (includes small indels) | 8/26 (~30.8%) (includes small indels) | Undefined | See above |
| Kergourlay et al. (2014) | DYSF (various exons) | Missense mutations reported as disease-causing | 5/24 (~20.8%) | 5/25 (20.0%) | Undefined | Muscular dystrophy (Bashir et al. 1998; Liu et al. 1998) |
| Mueller et al. (2015) | SMN1 exon 7 (54 bp) | All possible combinations of synonymous mutations within a sliding 2-codon window | Not reported | 32/138 (~23.2%)(includes both single and multiple mutations) | Bonferroni-corrected p value <0.05 in a Fisher’s Exact Test comparing the ratio of reads in the input DNA plasmid library to that in the output sample for the wild-type sequence vs for the mutant. In addition, PSI could be no more than 70% of wild-type levels | Spinal muscular atrophy (Lefebvre et al. 1995 ) |
| Soukarieh et al. (2016) | MLH1 exon 10 (94 bp) | All reported single-base substitutions (most from cancer patients) | 13/18 (~72.2%) | 17/22 (~77.3%) | PSI more than a single standard deviation removed from that observed in wild-type (standard deviation from three replicates) | See above |
| Julien et al. (2016) | FAS exon 6 (63 bp) | All possible single and almost all possible double mutations | 58/63 (~92.1%) | 115/189 (~60.8%) | p < 0.05 in Welch’s unequal variances t test comparing wild-type to mutant (3 replicates for either) | autoimmune conditions (Cheng et al. 1994 ; Fisher et al. 1995 ) |
| Tajnik et al. (2016) | FIX (F9) exon 5 (129 bp) | Haemophilia B associated single-base substitutions, selected either because their disease-causing mechanism was unclear or because they were located in a region thought to contain splice enhancer elements | 6/9 (~66.7%) | 9/17 (~52.9%) | Undefined | Haemophilia B (Bolton-Maggs and Pasi 2003) |
The column entitled proportion of splice-disrupting variants reports the fraction of tested variants that were classed as splice-altering. The column proportion of splice-associated sites contains the fraction of tested sites in the exon where any splice-altering variants were detected. Unless otherwise noted, only single-base substitutions are considered. The column definition of splice alteration details the criteria used in the study for classifying a variant as splice-altering. Only exonic variants are considered
Italicized rows correspond to studies classed here as belonging to the second subtype (studies that chose the variants to test in an unbiased manner)