Rare diseases affect nearly 300 million people globally with most patients aged five or less. Traditional diagnostic approaches have provided much of the diagnosis; however, there are limitations. For instance, simply inadequate and untimely diagnosis adversely affects both the patient and their families. This review advocates the use of whole genome sequencing in clinical settings for diagnosis of rare genetic diseases by showcasing five case studies. These examples specifically describe the utilization of whole genome sequencing, which helped in providing relief to patients via correct diagnosis followed by use of precision medicine.

Glioblastoma (GBM) is one of the most malignant forms of cancer with the lowest survival ratio. Our study aims to utilize an integrated bioinformatic analysis to identify hub genes against GBM and explore the active phytochemicals with drug-like properties in treating GBM. The study employed databases of DisGenet, GeneCards, and Gene Expression Omnibus to retrieve GBM-associated genes, revealing 142 overlapping genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the role of these genes, which were involved in cancer-associated cell signaling pathways with tyrosine kinase activities and mainly enriched in the Nucleus. Furthermore, the hub genes identification through Cytoscape identified the top 10 ranked genes in a network, which were used as targets to dock against phytochemicals retrieved from the NPACT database having the ability to pass the blood-brain barrier and drug-likeness properties. The molecular docking and dynamics simulation studies predicted the binding of Isochaihulactone and VismioneB to the active site residues of EGFR and SRC genes. In contrast, Resveratrol binds to key residues of PIK3CA. Further, the binding free energy of the docked complex was calculated by performing MM-GBSA analysis, providing a detailed understanding of the underlying molecular interactions. The results offer interactional and structural insights into candidate phytochemicals towards GBM-associated top-ranked proteins. However, validation studies must be done through both in vitro and in vivo disease models to strengthen our computational results.

Interleukin 17 F is a member of IL-17 cytokine family with a 50% structural homology to IL-17A and plays a significant role either alone or in combination with IL-17A towards inflammation in Rheumatoid arthritis (RA). A growing number of drugs targeting IL-17 pathway are being tested against population specific disease markers. The major objective of this research was to investigate the anti-inflammatory effect of Anakinra (an IL-1 R1 inhibitor) and Ustekinumab (an IL-12 and IL-23 inhibitor) by targeting IL17F. The three dimensional structures of IL17F was taken from PDB while structures of drugs were taken from PubChem database. Docking was performed using MOE and Schrodinger ligand docking software and binding energies, including s-score using London-dG fitness function and glide score using glide internal energy function, between drug and targets were compared. Furthermore, Protein-Drug complex were subjected to 150 ns Molecular Dynamics (MD) Simulations using Schrodinger's Desmond Module. Docking and MD simulation results suggest anakinra as a more potent IL17F inhibitor and forming a more structurally stable complex.Communicated by Ramaswamy H. Sarma.

High-throughput genome-wide sequencing has revealed high genomic variability of HPV16 in different geographic regions which is the most predominant genotype in human papillomavirus (HPV)–associated malignancies. Analysis of the HPV16 by whole-genome sequence (WGS) is an advanced method for the identification of mutations in the genome. There is limited information about HPV16 diversity in Pakistan, especially at the genomic level. Till now, WGS for HPV16 has not been previously reported in Pakistan. The current study has sequenced three HPV16 viral genomes, from two cervical and one oral cavity positive sample of women presented with general gynecological problems without any evidence of precancerous or cancerous lesions using an ion ampliseq customized panel. Sequencing analysis detected 38 variations, including single-nucleotide polymorphisms (SNPs) and two Indels, across three samples with the highest number of SNPs present in E1, E2, and L2, respectively. A total of 20 non-synonymous and 11 synonymous mutations with amino acid substitutions (T1421C, G1515A, T2223C, T1389C, G1483A, and T2191C) were identified. The phylogenetic analysis revealed the genomes of HPV16 are closely associated with those reported from Thailand and the United States. These are the first HPV16 WGS from Pakistan. However, more research is needed with a large sample size from diversified areas to assess the carcinogenic consequences and impact of HPV vaccinations.

Numerous studies have reported the polymorphisms in miR-196a2, miR-499 and miR-146a were associated with different types of cancers. However, the results have been inconsistent and varied. Therefore, we conducted a meta-analysis with the addition of the latest articles to explain the effect of these polymorphisms on Prostate (PCa) and Gastric cancer (GC). A total of 27 articles were recruited after a thorough literature analysis by two independent authors under the PRISMA guidelines in which 7 studies were related to PCa and 20 studies were of GC. We used STATA for performing the meta-analysis. The results from our analysis showed that miR-196a2 rs11614913 polymorphism is associated with PCa in allelic model in Asian population (CvsT: OR=1.207, 95%CI: 1.023-1.425, P=0.026), heterozygous model in Asian population (CvsT: OR=1.264, 95%CI: 1.008-1.585, P=0.042) while miR-499 rs3746444 is associated with PCa in allelic model overall population (AvsC: OR=1.201, 95%CI: 1.039 -1.388, P=0.013) and in Asian subjects (AvsC OR=1.23, 95%CI: 1.030-1.469, P=0.022). The miR-499 rs3746444 is also associated with GC in all four genetic models. Our results concluded that miR-196a2 rs11614913 and miR-499 rs3746444 may be involved in the development of PCa in Asian subjects while miR-499 rs3746444 may be related to GC prognosis