Whole Genome Sequencing as a Mainstay

0:06 Thanks for joining in today's session and over the next 30 odd minutes let us discuss whole genome sequencing as a main state the diagnostics. Before I start my talk there are few disclaimers to make. The opinions expressed in this session are my own and does not represent that of my employer or of aluminina and I'm being compensated for to speak at this session. Now my session starts with a bit of history and this history would range back to 50 odd years and many of you would be able to relate to what this instrument is. It is a CT scanner and a CT scanner was invented by Gfrey Houndsfield 50 odd years ago and in quick succession in the last 50 years it has become one of the main stays in the diagnosis for many specialtities including for example neurology.

0:58 And to put into perspective, 50 years ago, the only way you could actually peek into the human body was to essentially surgically open up the human body. And countless lives were lost due to surgical procedures in the first place to make a diagnosis. And the CT scanner actually put an end to that alto together making diagnosis much more faster much more efficient and saving countless number of lives.

1:30 I put this up because a similar technology has been sweeping or trillion cells that form the human body and that is the genome. And the human genome program that concluded in 2003 with the first draft would would entail that humans could peak into the blueprint of the human body. Not just of one human body but now accounting to millions of humans around the world.

2:09 India was not far behind in announced in the parliament way back in December 200 n you might ask patients with genetic condition typically lose 5 to 7 years before they can even get to a diagnosis. And a third of children actually die within the first 5 years. And a third of the sick, really sick children in the newborn eyes die even without having a diagnosis.

3:07 And this is largely array CG chromosomeal migrate to look at copy number changes mitochondrial sequencing to look at mitochondrial generator small scaleations and and duplications using MLPA and then using NGS and SA sequencing for smallite variants. We use a multitude of this genetic test. Some patients undergo multiple of this genetic test in sim in simultaneous succession.

3:40 And to me a whole genome sequence in very simplistic sense is our ability to sequence the genome and therefore the convergence of all of these genetic test making it very fast very cost effective and providing an end to the diagnostic. So in many simple sense a whole genome sequence can avoid many of these test being administered in tandem to the patient and it becomes a one single test which can solve the problem. Now how is it really important to get a first diagnosis? We come across a wide variety of disorders.

4:36 which we are not very well verssed at analyzing, interpreting, reporting or even talking to the patient and a whole genome of sequencing would take months altogether. Therefore, we don't have the time and energy to be able to order this. So the next 30 more minutes is to essentially debunk each of these points and to be able to whole genome sequencing can indeed a main state and let's take case of metabolic disorders what inborn error of metabolism quite very prevalent in population and it comes with extremely high mortality and mobility and a very narrow window of opportunity that would mean that if you can diagnose them very early on, they could actually be instituted therapy and they could leave a perfectly normal life. But for a wide large number of patients, they don't get to a diagnosis unless the the disorder really sets in, the pathology really sets in and it's often too late that the diagnosis can actually make any difference in the life of the patient because the window of opportunity is lost.

5:46 Now, how do we really change it? To me the data is already there and this is one such example from seat children's and what they did and and what they reported in 2025 was essentially to to convert all genetic test into one genetic test which is the whole genome sequence and the numbers I would say are quite remarkable. the time to diagnosis reduced from 289 days. That's approximately eight odd months to just two weeks or just around 13 days. That's largely because they did all the diagnosis on a whole genome sequence and the whole genome sequence can be done today quite very rapid and the same applies to sick children in the ICUs or the NICUs.

6:35 Consistent observations from across the world suggest that you can do whole genome sequence rapidly or even ultra rapidly. Ultra rapid would mean from 3 to 7 days of turnaround time and with consider very high considerable diagnostic yield of around 50 odd percent. And a right diagnosis in 3 to 5 days could mean a significant difference in the outcomes or the medical management of the child. In fact, rapid and ultra rapid genomes are currently available in India. In fact, we do offer ultra rapid genomes quite very routinely with a turnaround time of anything from 3 to 7 days and we could go much lesser than that in some cases. and this is one such case from Hyderabad where the the clinician making the decision to test the case to the time taken to release the report is under 48 hours.

7:32 And this is quite very transformative and in my opinion this is something that is going to be a routine as we speak as more and more sequences get done as more and more clinicians become well accustomed to whole genome sequencing. I think rapid and ultra rapid sequencing are become becoming the regular genome sequencing approaches in a few years from now. And given this advantages of diagnostic yield of the time the time reduction for diagnosis the ability to end the diagnostic OTC whole genome sequencing has already come to the guidelines. In fact, there are quite some guidelines currently including whole genome sequencing as a tier one genetic test.

8:17 This including this includes the American Academy of Pediatrics last year which included whole genome sequencing as a tier one genetic test for global developmental delay intellectual disability and abnormality. epileptic society using it as a tier one genetic test are increasingly adding whole genome sequencing into the guidelines and this is also because the diagnostic delay for some subclasses of genetic conditions are quite very significant like for example mitochondrial diagnosis a significant large number of patients with mitochondrial genetic diagnosis could have a diagnostic delay of 8.22 years just because of the fact that clinicians did not offer them the right test did not offer the right test because they did not suspect disorder in the first place.

9:27 In fact across populationing offers a broad test which includes the mitochondrial genome and this can significantly reduce the diagnostic delay. In fact there is evidence that a genomic sequence could significantly impact the undiagnosed and this is data from Kinger my code health. This is not not a whole genome sequence. This is an exom sequence which is all genetic conditions and in retrospective review of the electronic healthcare records they could show that a significant number had evidence already in the electronic healthcare records.

10:13 That means that they already have signs and symptoms which are consistent with the genetic condition but but nevertheless remain undiagnosed. So a genome as a tier one test, genome as a screening test, genome as an approach to reduce the diagnostic prote. The other quick question is how can we understand what is really prevalent in terms of genetic diseases because we call them as rare genetic diseases. Yes, individually they might be rare. There are around 7,000 to 10,000 autogenetic conditions and individually indeed they are rare but put together they they put together they encompass a very large proportion of the human genome.

11:02 Approximately one in 10 individuals today suffer from a genetic condition. But then how can you identify the prevalence estimates? The answer is very simple. All prevalence estimates today come from clinics. But we already know that there is a diagnostic OTC. There is a misdiagnosis and there's a delay in diagnosis of genetic condition. So data from the clinics might not be appropriate to understand genetic conditions. The other approach to me is to be able to look at the population scale genomes and the population scale genomes would understand will allow us to understand the carrier status of individuals and when two carriers marry you have a given probability of a recessive disorder to occur.

11:41 Now given this prevalence estimate you could go back to compare and contrast with what you get from the clinic and the gap is typically because of a diagnosis or a lack of diagnosis rather or a lack of diagnostic. Unfortunately, both of them can today be to be covered because if you have this information, if you know where the delay of diagnosis occurs, then you can cover them with adequate education, empowerment, with the right kind of diagnostics. Now, this is easier to say than than to do this. In 2019 with my colleague Shria we put together indigen India's first pilot scale population scale genome program which encompassed cosmopolitan thousand genomes from across India and the idea was can we identify the prevalence of extremely prevalent genetic conditions in the population and can we really use this as a public health decision-making data set now India is a very large country and to put numbers of a thousand is not going to be very representative just because of the fact that every one of thousand is going to represent a million of people but nevertheless having said that the real advantage being that the the prevalence estimates from this data would mean and impact millions of people across the country I'll just give a few examples of how we could use this data the first is for a genetic condition called primary immuno deficiency disorders the primary imun deficiency disorders are disorders of the immune system. Children with primary disorders cannot cannot fight infections and therefore they succumb to the infections. And this program was started in Kerala in my alma matter government medical college in Kolkat.

13:32 And the idea was given the high prevalence of the population genomic data for primary immuno deficiency disorders. We went back to the center created a plan for opening up a clinic very specialized to screen for primary deficiency disorder. offer genetic support in the clinic for prevalent disorders be able to screen the government with the research grant and only the virtual imunoglobins also government and apart from that number of individuals could access curative therapy which is heaptopic stem cell transplant or what we call as bone marrow transplant. Many many more families could prevent the recurrence of the disease in the family by genetic counseling and prenatal screening. And given the high prevalence of this disorder in the general population, we are currently piloting a newborn screening program for primary deficiency disorders, the first in the country to be able to do this.

14:45 The next obvious question is for treatable causes of intellectual disabilities. But before that, this is this is one of our first children who could get to diagnosis with a whole genome sequencing. with an early diagnosis, he could afford to have a bone marrow transplant which is also supported by the state. This is the patient along with his brother and this entire story was covered by the weak because this is one of the examples where genomics can actually make a difference in the lives of individuals.

15:15 Now when we talk about newborn screening the obvious question is what should be included in newborn screening programs and typically newborn screening programs a what is happening across the world and a significant component of disorders in the newborn screening programs are treatable causes of intellectual disability today encompassing around 10 104 odd genes and 80 disorders. Now can population scale genome data rationalize newborn screening programs? The answer is yes. And here what we did was to essentially look at the prevalence estimates of the pathogenic and likely pathogenic variants in this 81 odd disorders. And what we show is that some disorders are quite quite very frequent in the Indian population compared to the western population. This includes Wilson's disease, phenal ketoonura, bonus deficiency so and so forth which is almost 76 times more frequent in the Indian population in prevalence estimates compared to the rest of the world. In fact, we don't still have a newborn screening program for Wilson's disease. All biotin deficiency phenal keonura is included in some newborn screening programs but not all newborn screening programs.

16:23 Now given this fact what we think is that a genome scale program could have enormous value in rationalizing what needs to be included in newborn screening programs just because of the fact that Wilson's disease is a treatable prevalent genetic disorder. The carrier frequency of Wilson's disease in the general population amounts to approximately 1%. And it's not a surprise therefore that the NH is planning to sequence every child in the next 10 years and sequencing 100,000 or genomes under the NHS. And the idea is very simple. Can we sequence individuals to identify what is prevalent? what is penetrint, what is treatable with an affordable, accessible diagnostics, accessible therapy and there is a very high evidence for actionability and the ideas can be supplement the traditional newborn screening program which screens for a very slim or handful of genetic disorders using biochemical assays which have obvious problems in scalability or obvious problems in adding new genetic disorders with a much broader sequencing approach to be able to supplement to be able to improve the genetic diagnostic yield and be able to cover a significant large number of genetic disorders which are treatable today newborn screening.

17:51 So in other words, a newborn screening on genome sequencing. And in fact, you might ask, what is the data to support this? And in fact, a number of data points from across the world are emerging as we speak in the last couple of years. There's one snapshot from the Guardian program from Boston. And what they suggest is that a whole genome sequencing in an ethnically diverse individual group of around a 4,000 odd newborns would have a genetic diagnostic field of approximately 3.7%.

18:19 That means approximately one in every 30 odd children would have a genetic diagnosis. And this is quite very significant and almost 10 times the genetic diagnostic yield of a traditional newborn screening in the US which screens for approximately 37 all genetic conditions. Now given this fact the idea is can we now build the basis for such programs in different parts of the world. In India, we need to understand what is treatable with an affordable accessible therapy because what is treatable in the rest of the world might not be treatable in India with an affordable accessible therapy. So the only way to build this set of consensus is to be able to ask clinicians on what they think is treatable in their own ranks and this program was led by my colleague Dr. I and the idea was to essentially build a consensus document among clinicians with around 200 participating clinicians on what is treatable in the clinic with an accessible affordable therapy and the consensus document arrives at around 450 odd genes linked around 460 odd disorders which are treatable in India with an accessible affordable drug. Now compare and contrast this with what we currently run as newborn screening program which is a very small and minuscule part of this 400 or genetic disorders and this numbers are increasing as we speak.

19:42 The second paradigm is a genomic newborn screening is future proof and this is one such example. Spinal muscular atrophy is a very prevalent genetic disorder in India and in fact the cost of treatment for spinal muscular atrophy was enormously large amounting to almost 6 cr rupees perm making it out of reach for even the richest in the country. But then last year cot in Delhi struck down the patent of rristiplam making it a generic molecule in India with an Indian manufacturer driving the cost down to approximately 15,000 Indian rupees per month. That means approximately 1.5 lak rupees a year. But unfortunately not many children could access and can access this treatment because unless we screen for smile muscular atrophy we will never be able to put these children on therapy. So therefore the value of being able to screen using a broad test and using a broad genomic testing so that you can identify many more genetic diseases which can increasingly become accessible and affordable for treatment and not really wait for the treatment to arrive before the screen to happen.

20:58 And as we speak, we are in the juncture of a very interesting time in modern history. And that's our ability to sequence genomes at an unprecedented scale and at an unprecedented reduction in cost. They put the scale reduction and cost reduction. The cost of sequencing has dwindled almost a millionfold from the initial genome in the last two decades. And what this would mean approximately is genome sequencing which was designed to research laboratories and a handful of laboratories across the world would increasingly become a routine diagnostic test. And as we move it to a routine diagnostic test at scale as this price reduction continues unabated. This would largely mean a significant large number of people in the general population would also have their genomes done either as part of a newborn screening as part of the routine genetic workup of individuals or even as a screening program for apparently normal healthy individuals.

22:02 And as we speak, we also understand that a significant number of conditions that we thought were not genetic has a considerable genetic underpinning. This will include around a fifth of patients with dementia, a fifth of patients with sudden cardiac death or even approximately a third of patients with chronic kidney disease who have a genetic underpinninging. And this genetic underpinning could make a significant difference in not just the diagnosis but also the prognosis and treatment for these individuals. And as we speak many more specialtities as they sequence large/cohorts we we tend to understand a significant genetic underpinninging in these cohorts.

22:42 Now obviously the next question is what if we sequence normal people in the population. This data is from indigen which involved a thousand odd people from cosmopolitan populations in India apparently normal self-declared young empty individuals. And what we show is that one in 20 of these apparently normal individuals do have a genetic condition and more importantly these genetic conditions are treatable or what we call as medically actionable. Now roughly 2% of individuals in the Indian general population do have risk for cardiovascular disease, high penetrance risk for cardiammyopathy, cardiac channelopathy or familial hypoglymia and another 2% would have a genetic risk for heritary cancers just because they would have a high penetrance gene like braa 2 or MSH2 MSH6.

23:32 Now this would mean a lot because these are modifiable risk in some ways. In some cases this are aminable to early diagnosis, early treatment and in some cases preventative or curative treatments also. And in fact this is consistently now observed from multiple literature around South Asia not just in India. This is a recent literature which suggests that 1.2% of South Asians do have a cardiammyopathy variant. And you would have seen a number of news articles of young individuals who drop dead in the gym. And this is what we call as sudden cardiac death. In fact, 2% of Indians do have a genetic predisposition to sudden cardiac death. The lifestyle modification or even avoiding going to stren exercises or taking to the gym would essentially their hearts from failing.

24:28 And they could even live normal life with treatment in man for one pa 2 with almost one in 15 individual in the general. Put this into perspective. Braan Braha 2 comes in females with almost 50 to 80% lifetime risk of developing blaster ovarian cancer. In fact, it is amenable to early diagnosis and early treatment in some guys prevention and this would make a lot of difference because a stage one or stage two breast cancer in India is almost curable but a stage three or stage four which most almost 75% of women in India get diagnosed in stage three or stage four cost a lot to treat and comes with very poor outcomes. We use genomics to identify individuals at high risk, put them to an early high-risk program, screening program, be able to diagnose them early and in some cases at least prevent the disease and that would be an enormous opportunity. The third part of it is pharmaccogenomics which is an emerging area on using genetic information to avoid drugs which could cause adverse drug reactions or to be able to dose the drugs appropriately based on your phicodnamics and phicokinetics. In fact the indigent program provides an estimate that around eight every individual would have eight clinically actionable phoggenomic variants. Some of these phoggenomic variants are quite very prevalent including for CIP2C19 star to start to homozygous would mean you would need a dosage modification for some drugs like chloropl which is widely used in the Indian population. Now this is an enormous opportunity because a significant large number of drugs almost 100 odd drugs today are covered under either boxed labels or under clinical guidelines for pharmaccogenic testing before the administration. And that would broadly also mean that the scope of genetic testing is not just for the diagnosis but could now also extend to disease classification to disease management with pharmaccogenomic to disease prognostication. their prognostic algorithms which could include genomic data for family hypoglymia for PKD for polycystic kidney disease so forth and more importantly to be able to diagnose individuals early for prevention of onset or even early diagnosis and early treatment or other words the scope of genetic testing has far moved from diagnosis to disease classification to disease management disease prognostication and more importantly to be able to offer them early diagnosis and early treatment.

27:32 I'll give you just one example of this individual who got a genome sequence is a young individual 50 odd years. He did not have any apparent genetic disease or history of a genetic disease. But the genome sequence revealed familial hyperolmia. He had a genetic variant in the LDLR gene and family hypertomia heterrozygus could be treated very well with statins. But in India the statin phoggenomics is very important because a significant large number of individuals are predisposed to statin associated myopathy. So the genome sequence can offer not just the diagnosis of ML hypochristmia but also the ability to treat with the right kind of statins at the right dosage of statins so that the individual can remain as a productive individual in the society. I think that is the opportunity that we need to take forward and before I close there are few take-home points. genome sequencing and is becoming more affordable than ever and that means it would rapidly move into clinical implementation as a tier one genetic test. A genome sequence can enable a disease diagnosis in a patient or even in individual but at a genetic diseases are not rare.

28:48 Cumulatively they could mean approximately one in 10 individual has a genetic condition and therefore genomes are for everyone not just for patients but even for apparently normal individuals who could use genomic sequence to diagnose or pre-diagnose their condition and since your genome sequence is constant from womb to tomb it's also a test for a lifetime think I'll stop there but before I stop you can see that whole genome sequence this video possible. We are the first generation who could afford to have a whole genome sequence and therefore we should call ourselves the genome generation.

29:29 Thank you very much and you can reach out to me on social media or on email. I could take questions.