How sporadic are the rare diseases? Around 30 million Europeans, 25-50 million Americans and around 8% of the current Australian population suffer from a rare disease. Not all of these are inheritable, but many of these rare disorders and diseases are genetic. These diseases pose a significant challenge for clinicians and other healthcare providers. In most cases, not only are these diseases difficult to diagnose, but they are also challenging to treat.
The emergence of next-generation sequencing (NGS) has opened new possibilities for the timely detection and treatment of rare disorders and diseases. The easy availability of tools for methods like single cell RNA seq analysis has highlighted the relevance of mosaic and de novo mutations, SNPs, and digenic inheritance. NGS has reduced the cost of DNA sequencing, thereby making it possible to detect genetic diseases within a short period on a tight budget.
The ready access to data analysis and storage platforms makes it possible for researchers to compare similar data sets from patients.
Here are six ways in which NGS has helped in the prevention and cure of deadly diseases –
i. Advances in diagnostic technologies
Genetic analysis is no longer the final stage of diagnostic procedures for patients with rare diseases. The advancement of sequencing technology allows the detection of mutations in a single gene or within a set of genes. For example, using single cell RNA seq analysis one can determine the difference between the gene expression between healthy and diseased cells from the same location.
Advances in NGS technologies has given rise to a new process – reverse phenotyping. The use of NGS and segregation analysis together can identify pathogenic mutation(s) that researchers had attributed to different phenotype. Further retrospective study of the patient and his/her family members can lead researchers to find previously undetermined features influenced by the mutation(s).
ii. Rapid isolation of disease-causing gene(s)
Ever since the acceptance of NGS in mainstream diagnostics, several novel disease-causing genes and mutations have come to the limelight. In the last ten years, the total gene discovery for rare genetic diseases has increased by more than 2.4-times owing to the use of NGS platforms.
Currently, three NGS-based tests are leveraged for the research of rare diseases. Among all three, Whole Exome Sequencing (WES) is the most effective in identifying genetic aberrations and/or mutations responsible for a non-wild type phenotype. WES and single cell RNA seq analysis have been successfully used in recent research to identify the causal factors of metabolic disorders, neurodevelopmental disorders, myopathies, demyelination disorders and movement disorders in children and adults.
iii. Development and enrichment of gene panels
Gene panels are the coding regions of disease related genes that are targeted by highly specific probes during sequencing reactions. The use of single cell RNA seq analysis allows the comparative analysis of the gene expression between diseased and healthy cells. That helps in the determination of gene function and regulation in either cell types.
Gene panels are more powerful than micro-array based CNV detection. Interestingly, several studies around the globe have already employed gene panels for clinical diagnosis. However, their rates of correct diagnosis vary significantly.
Many of these studies involve rare conditions like orodental diseases, neuromuscular disorders, motor neuropathies, amyotrophic lateral sclerosis (ALS), cardiovascular disorders, intellectual disability, hematologic diseases, retinal disorders, cystic kidney diseases, juvenile diabetes, ichthyosis, aortopathies, metabolic disorders and epilepsy. The use of single cell RNA seq analysis to explore the heterogeneity of transcriptome expression in individual cells can help enrich the panel of genes responsible for pathogenesis.
iv. Discovery of the phenotypic spectrum of genes
Most genes don’t share a one-to-one relation with phenotypes. They have a phenotypic spectrum that is wide and varied. It contradicts initial beliefs about gene functions, but, in truth, a single gene can not only express diverse but disparate functions depending upon the mutation it bears.
A close look at the Online Mendelian Inheritance in Man (OMIM) database shows that a single mutation can be involved in multiple diseases. Many of them express different modes of inheritance as well. There is a strong possibility that the list of genes and their mutations responsible for rare diseases will keep growing as research teams keep exploring the phenotypic spectrum of genes by leveraging NGS.
v. Exploring digenic and polygenic inheritance
The world of digenic and polygenic inheritance was a mystery before the advent of new-age technology. NGS has allowed researchers to explore the entire spectrum of variants involved in digenic and polygenic diseases. Post identification of the disease causing mutation(s) in the involved genes, further analysis can reveal the nature of regulation and inheritance.
Most of the genetic data is already available in the Human Genome Project, The Cancer Genome Atlas (TCGA) and the OMIM. One of the most recent discoveries include the detection of heterozygous mutations in the GUCY1A3 and CCT7 genes. These are functional related genes that show digenic inheritance like the PINK1 and DJ-1 genes involved in Parkinson’s disease.
vi. Improvement of prognosis and disease treatment
NGS methods like single cell RNA seq analysis save cost and time. NGS methods can detect serious and life-threatening diseases at early stages. That makes room for proper treatment and improves a patients chances of survival. NGS opens doors for more effective treatment for several rare diseases.
NGS is elucidating the cause and treatment pathway for rare and chronic diseases. It is creating multiple targets for personalized drugs. Since a rare disease pathway may overlap with another common disorder/disease pathway, it leaves room for targeted treatment.
Today, the ongoing work on the development of gene panels facilitates the possibility of early detection or even prevention of certain deadly diseases. The early detection enables the patients to opt for better treatment options. In short, the introduction of NGS into the world of diagnostics has contributed to the study of de novo mutations in rare diseases, co-occurrence of multiple genetic diseases in one patient, and digenic inheritance.
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