Title | Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Soens, ZT, Branch, J, Wu, S, Yuan, Z, Li, Y, Li, H, Wang, K, Xu, M, Rajan, L, Motta, FL, Simões, RT, Lopez-Solache, I, Ajlan, R, Birch, DG, Zhao, P, Porto, FB, Sallum, J, Koenekoop, RK, Sui, R, Chen, R |
Journal | Hum Mutat |
Volume | 38 |
Issue | 11 |
Pagination | 1521-1533 |
Date Published | 2017 Nov |
ISSN | 1098-1004 |
Keywords | Alleles, Chromosome Mapping, Computational Biology, Exons, Gene Expression, Genes, Reporter, Genetic Association Studies, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Genetic Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Molecular Sequence Annotation, Pedigree, Reproducibility of Results, RNA Splicing |
Abstract | The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines. |
DOI | 10.1002/humu.23294 |
Alternate Journal | Hum Mutat |
PubMed ID | 28714225 |
PubMed Central ID | PMC5638688 |
Grant List | R01 EY009076 / EY / NEI NIH HHS / United States / / CIHR / Canada R01 EY022356 / EY / NEI NIH HHS / United States P30 EY002520 / EY / NEI NIH HHS / United States R01 EY018571 / EY / NEI NIH HHS / United States T32 GM008307 / GM / NIGMS NIH HHS / United States R25 GM069234 / GM / NIGMS NIH HHS / United States T32 EY007001 / EY / NEI NIH HHS / United States S10 RR026550 / RR / NCRR NIH HHS / United States |
Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance.
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