Massive Scale Genome Revolution: Changing the Rare Diseases Landscape – ETHealthworld.com

by Dr Firoz AhmadThe landmark completion of the human genome project in 2003 and its subsequent refinement has undoubtedly marked the beginning of a new era for biomedical research. The human genome project helped us to understand the most accurate sequence of the 3 billion DNA base pairs that make up the human genome. With this development, we have witnessed a paradigm shift in which medicine became personalized, predictive and preventive especially in fatal disease like cancer and other chronic diseases. There has been growing interest in expanding these success stories to Rare diseases (RDs), which are often progressive, frequently devastating and life-threatening clinical conditions. Although RDs affect a limited fraction of individuals from the general population (1 in 5000 people or less in Indian context), in aggregate they represent a substantial challenge to global health systems.There are approximately 5,000 to 8,000 different rare diseases globally, and it comes in many forms and includes some cancers, auto-immune diseases, metabolic conditions, blood disorders, neurological disorders and inherited malformations. Available literature suggests that India is home to nearly 70 million affected people with rare diseases, and some of the common examples are primary immunodeficiencies, hemoglobinopathies, muscular dystrophies, Lysosomal storage disorders, Niemann-Pick Disease, Ethylmalonic Encephalopathy, familial hypercholesterolemia, Mucopolysaccharidoses type I and type II, Rhizomelic chondroplasia punctata type 1, pseudorheumatoid dysplasia, ichthyosis, dystrophic epidermolysis bullosa, sporadic acrokeratosis, Tay-Sachs disease, Von Willebrand disease, Werner syndrome, Spastic Paraplegia 79 and many more. Majority of these diagnosed RDs are so rare that it is extremely difficult to identify clinically, patient may need 7-8 medical consultations, and at times it takes several years to come to conclusive diagnosis (Fig-1). As far as the etiology of the RDs is concerned, the exact cause for many rare diseases remains unknown. Still, for a significant portion, the problem can be traced to mutations in a single gene (genetic origin).As these conditions are tough to recognize clinically, genetic and genomic testing have become the backbone of diagnostic modality in recent times. Identification of pathogenic DNA changes remained a big challenge in earlier days (late 70s), wherein basic information about the DNA sequence and genomic location of a abnormal gene had to be worked out through a tedious, time consuming and expensive laboratory process called cloning followed by first generation sanger sequencing of the cloned product. Technological progress in DNA sequencing spurred after 2003, with the introduction of first high-throughput sequencing (Next Generation Sequencing, NGS) technology by Roche in 2005, capable of detecting genetic variation with high precision and accuracy. In no time, NGS became the true game-changer and brought a complete Genome Revolution by offering the capability to read the entire genomes, rather than individual genes. This gave researchers the ability to identify potential disease-causing variants across the genome much more rapidly than had previously been possible. Last one and half decade has seen rapid progress in the NGS technologies in terms of sequencing chemistry, data output, longer read lengths and improved bioinformatics tools. This has significantly increased the outputs of sequencing data in the gigabase range per instrument run, resulted in much affordable cost compared to the traditional Sanger first-generation sequencing method, and at a much quicker pace. Today, broader multigene panels (checks few clinically relevant genes), whole exome sequencing (checks all the coding exons of the genome, WES), clinical exome sequencing (checks approx. 6000 genes known to cause human diseases, CES), and whole genome sequencing (checks all exons and non-coding regions of the genome, WGS), are the most preferred testing methodologies in RD diagnosis. Patients are now increasingly liberated from the long-standing diagnostic bottleneck. Many can receive a diagnosis in just 2-3 months using modern day genomics tools in comparison to 7-8 years of traditional way, with a precision that remains unparalleled in medicine.

Generally a referring doctor considers high end genomic testing, if a patient visits to his/her clinic with non-specific overlapping symptoms and unexplained illness, or known to have several affected family members, or couples who have undergone consanguineous marriage. Furthermore, many paediatricians prefer to do genomics testing if they see early disease onset in a child or repeated episodes of seizures in newborn babies. As depicted in (Fig-1), the strategy begins with collection of detailed clinical information of the patient and his/her family history. Based on the clinical suspicion and past knowledge on the molecular etiology of the suspected disorders, two different approaches are considered for the genetic screening. In case of clinically suspected but genetically characterized RDs, screening of known disease-associated candidate genes through a multigene targeted panel or Clinical exome based NGS approach is recommended.

Thanks to this recent technological advance in genomics, the number of Mendelian diseases that have a known genetic cause went from 1,257 in 2001 to 4,589 in 2022 . The Genome Revolution has opened the door for true personalization in disease management, and it is now truly improving peoples health. With several success stories emerging globally including India, genomics will become a mainstay for diagnosis of rare genetic diseases in the near future.

by Dr Firoz Ahmad, Section-Head, Molecular Pathology, SRL Diagnostics, Mumbai

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Massive Scale Genome Revolution: Changing the Rare Diseases Landscape - ETHealthworld.com