Genética Humana e Embriologia

Cav1.4 is a retina-specific voltage-dependent Ca2+-channel that plays a regulatory role in sensory neurotransmission. Mutations in CACNA1F, encoding the conductive α1F subunit of Cav1.4, cause distinct eye dystrophies, including congenital stationary night blindness (CSNB), cone-rod dystrophy, and Åland eye disease. CANCA1F mutations detected in CSNB patients may be casual for the disease, however, the lack of functional validation prevents the provision of a diagnosis, and therefore, novel therapeutic targets. We have devised a protein-specific model that can predict the pathogenicity of these mutations that needs functional validation. 

Membrane proteins like Cav1.4 are translocated from the endoplasmic reticulum to the plasma membrane, within Golgi vesicles. However, missense mutations may cause protein misfolding events that can reduce the level of expression, mislocalisation, and decrease the function. The misfolding of mutant proteins can be rescued by small molecules, such as chemical chaperones that stabilise protein folds and reduce non-native interactions, or proteostasis regulators that enhance protein folding and trafficking. Both classes of molecules can protect mutant proteins from degradation. 

This suggests that small molecules have great potential as a valuable therapeutic approach for treating retinal, and other, protein misfolding diseases. I will use CSNB as an exemplar of this in this project to test the pathogenicity of novel CSNB variants of unknown significance identified in Manchester Centre for Genetic Medicine NHS diagnostic laboratory. These variants will validate our inhouse prediction tool and test the effect of small molecules on protein expression, localisation, and function.

Cell growth and/or proliferation may require the reprogramming of metabolic pathways, whereby a switch from oxidative to glycolytic metabolism diverts glycolytic intermediates towards anabolic pathways. Herein, we identify a novel role for TRIM32 in the maintenance of glycolytic flux mediated by biochemical interactions with the glycolytic enzymes Aldolase and Phosphoglycerate mutase. Loss of Drosophila TRIM32, encoded by thin (tn), shows reduced levels of glycolytic intermediates and amino acids. This altered metabolic profile correlates with a reduction in the size of glycolytic larval muscle and brain tissue. Consistent with a role for metabolic intermediates in glycolysis-driven biomass production, dietary amino acid supplementation in tn mutants improves muscle mass. Remarkably, TRIM32 is also required for ectopic growth - loss of TRIM32 in a wing disc-associated tumor model reduces glycolytic metabolism and restricts growth. Overall, our results reveal a novel role for TRIM32 for controlling glycolysis in the context of both normal development and tumor growth.

A comparative study of the degree of influence of a drug being developed on microbial and eukaryotic cells is one of the important stages in the drug development.

This study examined the selective effect of a novel drug FS-1 on bacterial cells in the presence of eukaryotic cells.

The drug FS-1 is a nanocomplex of iodine and lithium and magnesium halides with dextrin and polypeptides, the molecular weight of dextrin enables penetration of active centers of the FS-1 molecule into the cells. Mycobacterium smegmatis ATCC 607 was used as a model system.

Data were obtained that indicate the effect of FS-1 predominantly on bacterial cells.

A new systems approach to diseased states and wellness result in a new branch in the healthcare services, namely, personalized and precision medicine (PPM). To achieve the implementation of PPM concept, it is necessary to create a fundamentally new strategy based upon the recognition of biomarkers and thus the targets to secure the grand future of drug design and drug discovery.

Each decision-maker values the impact of their decision to use PPM on their own budget and well-being, which may not necessarily be optimal for society as a whole. It would be extremely useful to integrate data harvesting from different databanks for applications such as prediction and personalization of further treatment to thus provide more tailored measures for the patients resulting in improved patient outcomes, reduced adverse events, and more cost effective use of the latest health care resources including diagnostic (companion ones), preventive and therapeutic (targeted molecular and cellular) etc.

PPM, genomics and AI are those of the most rapidly emerging areas of biomedical research and the most promising technologies for improving health care and health outcomes. Examples include the use of AI for improved DNA sequencing and SNP analysis to target specific cell and tissue types, biosensors for specific molecules in vivo, and point-of-care molecular diagnostic devices enabled by genomics- and AI tools.

The enormous development of genomics research has raised great expectations concerning its impact on PPM aiming to customize medical practice with a focus on the individual, based on the use of genetic tests, identification of genomic biomarkers, and development of targeted drugs. Personal genomics is an area of genomics focusing specifically on the sequencing and analysis of one person’s genome, and then giving them their genomic information.

The emphasis on individuals and genomic knowledge needs to be counterbalanced with the subjects’ understanding in their sociocultural, political, and economic contexts and with the equivalent investment in actions on the social determinants of health. The above-mentioned areas being an integral part of PPM is really an interdisciplinary research field that results from the application of the innovative genomic and AI tools to medicine and has the potential to significantly improve some canonical treatments, prevention, prophylaxis and

rehabilitation. Specifically, in the field of PPM, it is expected to have a great impact in the near future due to its multiple advantages, namely its versatility to adapt a drug to cohorts of patients and/or persons-at-risk. For instance, multimodal genomic and AI-driven approaches may indeed become a key driver in harmonizing the needs of the various stakeholders by allowing cost-effective delivery and monitoring of drug efficiency and safety, and close-meshed high-quality data collection.

Personal genomics can be used to advise couples wanting to have children. By knowing the risk of passing on a genetic disorder to their child, they may decide to investigate other ways of having a baby, such as in vitro fertilisation (IVF).

Meanwhile, personalized genomic medicine and surgery (PGMS) represents a new approach to health care that customizes patients’ medical treatment according to their own genetic information. This new approach is the result of increased knowledge of the human genome and ways this information can be applied by physicians in the medical and surgical management of their patients.

Currently, personal genome sequencing and testing is a relatively niche market with a number of services available over the internet. However, the commercialization of personal genome sequencing is set to grow and, in future, it could become a routine part of clinical practice.

Genomic research and thus the market offer clinicians new techniques for risk assessment and disease classification. However, the scope of this new testing paradigm remains to be determined. Genetic tests should be seen as the latest set of tools to assist clinicians and patients in the decision-making process. Some genetic tests will undoubtedly play an important role in identifying individuals with high risks for preventable disease, or in refining clinical diagnoses. Irrespective of the number of genetic tests that prove clinically useful, genomic research will continue to provide essential new information about how and why diseases occur.

The promise of PPM is well understood and exists at the convergence of genomic sequencing, biomarker research, and big data analysis. One of the big challenges to bringing more lifesaving PPM-based treat treatments to patients is that the vast networks of hospitals, foundations, and other organizations working toward new treatments and cures lack consensus on how to pursue their common goal.

As a consequence, duplicative efforts and inefficiencies proliferate in this network. It will take a business mindset to overcome these obstacles.

By virtue of treating each person's condition as unique, personal genomics and PPM require health professionals to understand the nature of the data, its health implications, and its limitations. But the public understanding of the scope and impact of genetic variation has not kept up with the pace of the science or technology. We examine several venues for information, including print and online guides for both lay and health-oriented audiences, and summarize selected resources in multiple formats. We also stress that implementation of PPM thus requires a lot before the current model “physician-patient” could be gradually displaced by a new model “medical advisor-healthy person-at-risk”. This is the reason for developing global scientific, clinical, social, and educational projects in the area of PPM to elicit the content of the new branch. In short, PPM will transform the way doctor’s practice and will shake up the entire pharmaceutical value chain.

Hearing loss is one of the most common sensory disorders in humans with both genetic and environmental etiologies. Genetic causes of hearing loss are extremely heterogeneous; more than 100 genomic loci for hearing loss have been mapped so far. Usher syndrome (USH) is the most common cause of combined blindness and deafness inherited in an autosomal recessive mode. Molecular diagnosis is of great significance in revealing the molecular pathogenesis and aiding the clinical diagnosis of this disease. Our study aims to comprehensively delineate the genetic basis of hearing loss in the individuals of Saudi Arabian origin.

The identification of the causative gene in affected families with hearing loss is difficult due to extreme genetic heterogeneity and lack of phenotypic variability. Consanguineous families are a powerful resource for genetic linkage studies/homozygosity mapping for recessively inherited hearing impairment. Homozygosity mapping, linkage analysis and next generation sequencing Deafness Gene-panel and Whole Exome sequencing were conducted. Using the combined approaches, so far mutations in 32 different deafness genes have been identified in 300 familial/sporadic cases, including novel variants in known HL genes and novel genes. 

Using these innovative molecular approaches, we were able to document the most common forms of hereditary hearing loss, their incidence and distribution in the Saudi population. The overall results of this study are highly suggestive that the underlying molecular basis of hearing loss in Saudi Arabia is very genetically heterogeneous. The benefit of this study will hopefully provide the foundation for knowledge and awareness through screening of carrier status and genetic counselling, thereby having a major impact upon early intervention for and prevention of hereditary hearing loss.

DNA repair is a critical process to maintain DNA integrity. It is conducted by distinct pathways of genes, many of whose alterations are thought to result in genomic instability and hypermutability, ultimately contributing to tumorigenesis. Tumor Mutation Burden (TMB) and Microsatellite Instability (MSI) are considered as immunotherapy efficacy biomarkers.  However, there has been little characterization of the association between DNA repair genes and TMB/MSI in cancer. 

We systematically analyzed 282 DNA repair genes involved in 20 DNA repair pathways.  These genes were evaluated for mutations based on 274 sequenced tumor samples from the TCGA database.  The functional impacts of these mutations were analyzed, and only damaging mutations were used for the subsequent analysis.  The most frequently mutated genes were identified.  The association between the damaging mutations and TMB/MSI status was calculated for each gene, and the significant genes were subject to further pathway enrichment analysis. We also compared the gene expression between TMB high and low as well as between MSI-H and MSI-L/MSS for each gene based on their RNAseq data. The potential associations with TMB/MSI high phenotypes were evaluated. 10 genes, including POLE, were identified that are significantly mutated in TMB high samples as compared to MSI-H samples. Loss of function of these genes may result in an ultra-mutated phenotype. Contradicting the notion that POLE mutation is predominantly associated with MSS tumors and are mutually exclusive with the complete loss of MMR, we found about half of POLE-mutant samples (8/16) were MSI high, five of which had MMR mutations.

The present study was undertaken to develop Vitamin D and Calcium rich products using different cooking techniques. Products were prepared using Sundried Mushroom Powder; Ragi Flour, The development of technologies to sequence millions and ultimately billions of individual DNA molecules simultaneously has been called next generation sequencing (NGS). A much better term, however, would be to call it what it is, which is massively parallel sequencing (MPS). The advances in MPS have been phenomenal and in the past 13 years the output on MPS platforms has increased from 20 megabases per run to now over 7 terrabases. First generation MPS is based upon the amplification of individual molecules prior to sequence interrogation. The output and accuracy of these platforms has been outstanding, at the sacrifice that only short DNA molecules could be analyzed. Second generation MPS is based upon sequencing individual molecules which is now capable of analyzing molecules that are hundreds of thousands of base pairs long. However, this comes at the sacrifice of output and sequence accuracy. With both first and generation MPS platforms it is now possible to sequence entire genomes, exomes, targeted genomic regions, and even genome-wide methylation. In my talk I will summarize the history of different MPS platforms and then discuss where we are today and where we should be in the next few years. MPS technologies have the capability of changing how we both look at genomes and ourselves.

I am pleased to mention that during the year 2018, all issues of volume 8 were published online well within the time and the print issues were also brought out and dispatched within 30 days of publishing the issue online.

Human Genetics & Embryology during this year also brought out 10th International Conference on Human Genetics and Genetic Diseases proceedings, which consisted of ~ 20 abstracts.

The Journal Impact Factor HGEC for the year 2018 was 1.04 while the indexing of the journal was however, increased to Index Copernicus; Google Scholar; Sherpa Romeo; Open J Gate; Genamics JournalSeek; CiteFactor; RefSeek; Hamdard University; EBSCO A-Z; OCLC- WorldCat; Publons