When 30 year old Rohit Nair woke up with palpitations, he was convinced it was pressure from his high stakes corporate job that was affecting his heart. His cardiologist thought the same, and an angiography revealed blockages that seemed to confirm it. However, something about the way they appeared on image spurred his doctor to look deeper. 

Biochemical tests revealed that Rohit had raised amounts of a compound called homocysteine in his blood, to a level that has been associated with coronary artery disease [1]. When physicians tried to find the underlying cause for long term treatment, it was genetic testing that provided the missing piece of the puzzle. Rohit was found to carry a defect in the MTHFR gene, responsible for homocysteine metabolism in the body. 

He was started on medication to lower homocysteine levels, and advised regular supplements of B12, a vitamin that helps in homocysteine breakdown. Timely intervention from a young age now drastically lowered his chances of developing the cardiac issues that he would otherwise inevitably have, due to this genetic anomaly. Every so often, a case like Rohit’s comes to attention, showing us that the key to many mysteries about our health lie in our genes and emphasizing the need for looking at them closely.

Our genes contain a blueprint of our physical, physiological, even behavioral characteristics. Humans have two copies of each gene, arranged as two sets of 23 chromosomes, one from each parent. Occasionally, errors called ‘mutations’ can creep into the DNA sequence of one or more genes, and genetic instruction can be changed or lost. Disease or disorder may result, and symptoms become apparent. 

Some genetic variations, while not causing illness themselves, may increase an individual’s susceptibility to certain diseases. The sum total of genetic material that a person has is called their ‘genome’, and ‘genomics’ refers to the study of a person’s overall genetic landscape.

‘Next generation Sequencing’ (NGS), a technique harnessing advanced microfluidics and massive computational power, has revolutionized the speed and efficiency of deciphering genetic errors through DNA sequencing. NGS is being used in advanced genetic laboratories around the world to sequence people’s genomes, and uncover critical information about their current health, future risks, metabolic patterns, and possibility of passing on heritable conditions to their children (carrier risk). 

The ‘Genomic Health Insight’ or GHI test by Strand Life Sciences brings the many benefits of genomic testing to the broader Indian population The test uses NGS to sequence over 20,000 genes  and identifies 35,000 to 45,000 possible variants in these genes that make one’s genome unique. Then, these variants are carefully analyzed by scientists to assess if they pose any significant risk for disease in the future, or underlie some present condition that has gone undetected. This includes risk for 12 types of hereditary cancers, hereditary cardiovascular disease, and over 60 late-onset metabolic diseases. The GHI test also includes carrier risk screening, spanning over 190 hereditary conditions, and pharmacogenomic assessment of metabolic response to more than 100 commonly used drugs. 

A quick look at the findings of the GHI test shows us how meaningful its results can be, even in a relatively small sample of ~80 presumed normal individuals. As many as 51% of tested individuals were found to harbor serious mutations in one of two copies of a gene associated with heritable disease, such as cystic fibrosis (CFTR), beta thalassemia (HBB), Pompe disease (GAA) etc. These individuals themselves are not at risk for disease on account of these mutations. However, if the tested individual’s partner also carries a  problematic mutation in the same gene by chance, their children will have a high probability of manifesting the disease, and consequent disability or death. Social practices of marrying within small communities or same families in India can cause certain rare, single gene  diseases to be more common for this reason.  

For example, multiple individuals were found positive for carrier risk mutations in the HBB gene, encoding a protein essential for the oxygen transporting functions of blood hemoglobin. HBB mutations are associated with beta thalassemia, a debilitating condition causing anemia, jaundice, growth failure, and compromised bones, spleen, liver, and heart function. Many people with beta thalassemia major require regular blood transfusions throughout their life (2). 

Since a majority of the tested individuals were of childbearing age (20 – 40 yrs), the implications of a carrier risk are especially relevant. Those with such a mutation can now take particular care when planning a pregnancy, and get their partner tested before it. If the partner tests positive, the couple can opt for prenatal genetic testing to see if the child has indeed inherited two mutated genes, and can make an informed decision about proceeding with the pregnancy. Knowing what disease symptoms to expect can also help initiate medical care or treatment for the baby as soon as possible, raising its chances of surviving and thriving. 

On the other hand, some individuals were found to have mutations in genes that significantly predisposed them to breast cancer – MSH6 and RAD51D. In fact, studies have shown that women with an MSH6 mutation had more than double the breast cancer risk of women without it, and 31 to 38% of those with such mutations go on to have breast cancer in contrast to ~10% otherwise  [3]. Breast and ovarian cancer are the most prevalent cancer and leading cause of death in Indian women, but early diagnosis and treatment can raise survival rates to above 90% [4,5]. 

Similarly, the GHI test revealed mutations in the KCNQ1 gene, associated with a cardiac condition called Long QT syndrome in the sampled population [6]. Once detected, an individual with these risks can ensure regular medical surveillance like mammograms or electrocardiograms, consider preventive measures such as hormone replacement therapy or risk reducing mastectomy, change any lifestyle factors that worsen the risk such as diet or heavy exercise, as well as test their family members in case they have the same mutation.

Another interesting insight GHI offers is pharmacogenomic, or how small sequence variations in the genes encoding drug metabolizing enzymes shape our individual responses to medication. These genetic differences translate into different levels of enzyme functionality in each individual, determining how effective a specific drug or dosage will be for them. This is very useful for tailoring a treatment plan that would work best, with minimal side effects, for each person, and is called personalized or precision medicine – an approach that is mindful of each individual’s unique genetic profile while choosing the most effective treatment route for them.

The physical risks of the GHI test are minimal (DNA obtained from blood sample or mouth swab), but it is important to understand properly what the results imply for a person and their family. Since different environments affect gene expression in different ways, risk does not necessitate a clinical condition. Symptom severity may be more or less, and disorder progression faster or slower, than expected. Thus an integral part of the GHI test is genetic counseling, to help each individual interpret their report.

Overall, the test yields personalized knowledge that can greatly improve not only our longevity, but also our quality of life. The value that tests like GHI bring to our lives can be appreciated by looking at the statistics of health and disease in India, such as that from a cross-cultural study conducted by Manchanda et al [7]. The study estimated that population based genetic testing had the potential to prevent approximately 790230 breast or ovarian cancer cases in India, and save about 255645 lives here from succumbing to these diseases.

 

Bibliography:

1. Puri, A., Gupta, O. K., Dwivedi, R. N., Bharadwaj, R. P., Narain, V. S., & Singh, S. (2003). Homocysteine and lipid levels in young patients with coronary artery disease. J Assoc Physicians India, 51, 681-5.
2. Galanello, R., & Origa, R. (2010). Beta-thalassemia. Orphanet journal of rare diseases, 5, 1-15.
3. Roberts, M. E., Jackson, S. A., Susswein, L. R., Zeinomar, N., Ma, X., Marshall, M. L., … & Chung, W. K. (2018). MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genetics in Medicine, 20(10), 1167-1174.
4. Kadri, M. S. N., Patel, K. M., Bhargava, P. A., Shah, F. D., Badgujar, N. V., Tarapara, B. V., … & Joshi, M. N. (2021). Mutational landscape for Indian hereditary breast and ovarian cancer cohort suggests need for identifying population specific genes and biomarkers for screening. Frontiers in oncology, 10, 568786.
5. Mehrotra, R., & Yadav, K. (2022). Breast cancer in India: Present scenario and the challenges ahead. World Journal of Clinical Oncology, 13(3), 209.
6. Stattin, E. L., Westin, I. M., Cederquist, K., Jonasson, J., Jonsson, B. A., Mörner, S., … & Wisten, A. (2016). Genetic screening in sudden cardiac death in the young can save future lives. International journal of legal medicine, 130, 59-66.
7. Manchanda, R., Sun, L., Patel, S., Evans, O., Wilschut, J., De Freitas Lopes, A. C., … & Legood, R. (2020). Economic evaluation of population-based BRCA1/BRCA2 mutation testing across multiple countries and health systems. Cancers, 12(7), 1929.