Rare diseases (RDs) are rare complex genetic diseases affecting a conservative estimate of 300 million people worldwide. Recent Next-Generation Sequencing (NGS) studies are unraveling the underlying genetic heterogeneity of this group of diseases. NGS-based methods used in RDs studies have improved the diagnosis and management of RDs. Concomitantly, a suite of bioinformatics tools has been developed to sort through big data generated by NGS to understand RDs better. However, there are concerns regarding the lack of consistency among different methods, primarily linked to factors such as the lack of uniformity in input and output formats, the absence of a standardized measure for predictive accuracy, and the regularity of updates to the annotation database. Today, artificial intelligence (AI), particularly deep learning, is widely used in a variety of biological contexts, changing the healthcare system. AI has demonstrated promising capabilities in boosting variant calling precision, refining variant prediction, and enhancing the user-friendliness of electronic health record (EHR) systems in NGS-based diagnostics. This paper reviews the state of the art of AI in NGS-based genetics, and its future directions and challenges. It also compare several rare disease databases.
Single nucleotide variants (SNVs) can exert substantial and extremely variable impacts on various cellular functions, making accurate predictions of their consequences challenging, albeit crucial especially in clinical settings such as in oncology. Laboratory-based experimental methods for assessing these effects are time-consuming and often impractical, highlighting the importance of in-silico tools for variant impact prediction. However, the performance metrics of currently available tools on breast cancer missense variants from benchmarking databases have not been thoroughly investigated, creating a knowledge gap in the accurate prediction of pathogenicity. In this study, the benchmarking datasets ClinVar and HGMD were used to evaluate 21 Artificial Intelligence (AI)-derived in-silico tools. Missense variants in breast cancer genes were extracted from ClinVar and HGMD professional v2023.1. The HGMD dataset focused on pathogenic variants only, to ensure balance, benign variants for the same genes were included from the ClinVar database. Interestingly, our analysis of both datasets revealed variants across genes with varying penetrance levels like low and moderate in addition to high, reinforcing the value of disease-specific tools. The top-performing tools on ClinVar dataset identified were MutPred (Accuracy = 0.73), Meta-RNN (Accuracy = 0.72), ClinPred (Accuracy = 0.71), Meta-SVM, REVEL, and Fathmm-XF (Accuracy = 0.70). While on HGMD dataset they were ClinPred (Accuracy = 0.72), MetaRNN (Accuracy = 0.71), CADD (Accuracy = 0.69), Fathmm-MKL (Accuracy = 0.68), and Fathmm-XF (Accuracy = 0.67). These findings offer clinicians and researchers valuable insights for selecting, improving, and developing effective in-silico tools for breast cancer pathogenicity prediction. Bridging this knowledge gap contributes to advancing precision medicine and enhancing diagnostic and therapeutic approaches for breast cancer patients with potential implications for other conditions.