Genomics Revolution In Rare Diseases' Diagnosis
Pregnancy is a happy period for every expecting couple. There is a lot of cheer in the family to welcome a new bundle of joy.
However, Tamilarasi, aged 27, pregnant with her second child, is spending sleepless nights since the time her doctor confirmed her pregnancy. Sitting on the verandah of her single-storied frugal house, in the interiors of Thiruporur, a small village in eastern Tamil Nadu, she breaks into occasional tears. Her first born, Manikandan, now 6 years old, has difficulty walking, running and jumping. Though he was a late walker, nobody noticed any abnormalities till he started looking clumsy, falling quite often, requiring palm support to get up after sitting, amongst others. She is now scared if her second child will have the same condition.
Manikandan was brought to the local doctor at the primary clinic, where few tests were done and no diagnosis was provided. The family then approached another local physician who also conducted a battery of tests without much information. After many such incidents and when Tamilarasi had almost given up hope, her brother-in-law’s friend referred them to a senior doctor in a leading hospital in Chennai. The doctor then counselled Tamilarasi and apprised her about the possibilities of a genetic disease. He ordered for genomic testing to be done immediately. The results identified Manikandan as affected with Duchenne Muscular Dystrophy (DMD).
DMD, a rare disorder, is a well-known type of muscular dystrophy which is a genetic condition portrayed by progressive weakness and degeneration of the skeletal muscles that control development. WHO defines rare disease as often debilitating lifelong disease or disorder with a prevalence of 1 or less, per 1000 population? However, different countries have their own definitions to suit their specific requirements and in the context of their own population, healthcare system and resources. These are diseases inherited from the parents, sometimes manifesting at Birth, or later in life, the information of which is present in the DNA.
Human DNA is like a string of letters. When a certain set of these letters give rise to a word or, in technical terms, form a protein, it is referred to as a gene. Like a word can have ‘silent’ letters, genes also have silent non-coding parts called Introns. The actual part of the gene which codes for the protein is referred to as Exons and the whole exon content of the cell is referred to as Exome. Although the exome makes up less than 2 per cent of the whole human genome, all of the protein-coding genes are found in the exome. Since most genetic disorders are correlated with mutations in protein-coding genes, most physicians and scientists who use sequencing technologies for diagnostic purposes start with an analysis of the exome. Exome sequencing and analysis typically takes less time than whole-genome sequencing, at less than half the cost.
In sequencing, depending on the test prescribed, the order of letters in your DNA is deciphered by scientific experts who specialise in Clinical Genomics. This team comprises Molecular Biologists, Geneticists and Bioinformaticians, who comb through the sequencing data to discover unusual genetic changes or mutations. Usually, the treating clinician then collaborates with this team to understand the results and counsel and treat his patient accordingly. Hence, if you have an illness that is tough to diagnose or a family history of health conditions, your physician might suggest genomic sequencing for additional hints. This has led to more rare diseases being diagnosed on a routine basis and hopefully, put an end to multiple clinic visits for anxious patients or their guardians.
Disorders as common as DMD or as rare as Progeria could have gone hitherto unnoticed. With the current advancements in Clinical Genomics, supported with awareness in the pandemic era, people like Tamilarasi do not have to undergo an odyssey of medical tests with multiple doctor visits anymore. Recent studies have shown that sequencing technologies can help identify uncommon gene mutations that cause a rare disease. These mutations tend to be undetected by conventional tests. These researches have, in some cases, led to more accurate diagnoses and better therapies. Precision in diagnosis, including the identification of disease subtypes, directly influences treatment and patient outcomes. Understanding of the illness at a molecular level is essential for the identification of many diseases and their subtypes. Comprehending the genomics of rare disease can help doctors pinpoint the cause of undiagnosed disorders, helping families avoid years of hospital visits and unnecessary tests. With the popularisation of molecular techniques like Next Generation Sequencing, MLPA and Advanced Polymerase Chain reactions, by efforts of diagnostic chains, genetic testing no more remains a niche area and has invaded the doctors’ prescription on a day-to-day basis.
With technical advancements and reduced costs, Clinical Exome, Whole Exome and Whole Genome Sequencing based on NGS technology are becoming more popular amongst clinicians for diagnosing rare diseases.
Tamilarasi heaved a sigh of relief. Her reports told her that the foetus was unaffected by DMD. She is busy preparing to welcome her baby to the world now.
Not far is a day when rare disease would not mean ‘rarely diagnosed’, but truly ‘rarely affected’, with genomics paving the way!
