Dataset Information

INDELpred: Improving the prediction and interpretation of indel pathogenicity within the clinical genome.

ABSTRACT: Small insertions and deletions (indels) are critical yet challenging genetic variations with significant clinical implications. However, the identification of pathogenic indels from neutral variants in clinical contexts remains an understudied problem. Here, we developed INDELpred, a machine-learning-based predictive model for discerning pathogenic from benign indels. INDELpred was established based on key features, including allele frequency, indel length, function-based features, and gene-based features. A set of comprehensive evaluation analyses demonstrated that INDELpred exhibited superior performance over competing methods in terms of computational efficiency and prediction accuracy. Importantly, INDELpred highlighted the crucial role of function-based features in identifying pathogenic indels, with a clear interpretability of the features in understanding the disease-causing variants. We envisage INDELpred as a desirable tool for the detection of pathogenic indels within large-scale genomic datasets, thereby enhancing the precision of genetic diagnoses in clinical settings.

SUBMITTER: Wei Y

PROVIDER: S-EPMC11321314 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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INDELpred: Improving the prediction and interpretation of indel pathogenicity within the clinical genome.

Wei Yilin Y Zhang Tongda T Wang Bangyao B Jiang Xiaosen X Ling Fei F Fang Mingyan M Jin Xin X Bai Yong Y

HGG advances 20240710 4

Small insertions and deletions (indels) are critical yet challenging genetic variations with significant clinical implications. However, the identification of pathogenic indels from neutral variants in clinical contexts remains an understudied problem. Here, we developed INDELpred, a machine-learning-based predictive model for discerning pathogenic from benign indels. INDELpred was established based on key features, including allele frequency, indel length, function-based features, and gene-base ...[more]

PMID: 38993112

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Project description:IMPORTANCE:Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES:To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS:An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES:Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS:Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross ?, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss ?, 0.24; P?<?001). CONCLUSIONS AND RELEVANCE:In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

Project description:Polymorphisms in pre-miRNAs may affect its expression, then having effect on its target mRNAs and be associated with cancer susceptibility. In the current study, we evaluated the association of a 3-base pair (3-bp) indel polymorphism (rs57408770) in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. To further investigated the molecular mechanism underlying the correlation between rs57408770 and the risk of HCC, overexpression of pre-miR-3131 in HCC cell line was performed. Human HCC cell lines Sk-Hep-1 was obtained from Shanghai Cell Bank of Chinese Academy of Sciences on 9 December 2013.The fragment of 366bp including the insert allele of rs57408770 in pre-miR-3131 was directly synthesized and cloned into BamHI and EcoRI sites of pEGFP-N1 yielding the wild-type vector (pEGFP-N1-miR3131-WT). The mutant-type vector (pEGFP-N1-miR3131-MT) including the delete allele of rs57408770 was generated using QuikChange Lightening Site-Directed Mutagenesis Kit. The resulting constructs were verified by direct sequencing. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5Î¼g plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000. After 24 hours of the transfection, the cells were collected for subsequent experiments.And human genome-wide gene expression profile assay was used to screen the targets of miR-3131. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5Î¼g plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000 (Invitrogen). After 24 hours of the transfection, the cells were collected for subsequent experiments. There are 3 samples in this experiment.

Dataset Information

INDELpred: Improving the prediction and interpretation of indel pathogenicity within the clinical genome.

Publications

INDELpred: Improving the prediction and interpretation of indel pathogenicity within the clinical genome.

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