“Many doctors still cling on to the old concept that genetic diseases have no treatment”

October 10, 2018 0 By CH Unnikrishnan

C H Unnikrishnan

Dr IC Verma, Professor and Senior Consultant Adviser, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, who is known as the father of human genetics in India, talks about the critical nature of the countrys genetic disease burden in an interview with C H Unnikrishnan. Edited excerpts:

  1. According you, what are the key factors that contribute to Indias increasing burden of genetic disorders?

Until recently infectious diseases and malnutrition have been the predominant cause of morbidity and mortality. With recent control of these diseases, genetic disorders have become more apparent. Earlier they were hidden by the overwhelming presence of infectious diseases.

Secondly, we have a huge population and large number of births (26 million per year), so that the total number of newborns, as well as older children and adults, with genetic disorders is the highest as compared to any other country.

Thirdly, because of the improved facilities of intensive saves many infants with acute genetic metabolic disorders, who would have otherwise died, thus increasing the pool of the children with genetic disorders.

Fourthly, in many parts of India, an increasing number of consanguineous marriages take place, especially among Hindus in South India and Muslim communities all over India. Consanguineous marriages increase the incidence of autosomal recessive disorders. Many communities do not practice consanguinity, but marry endogamously (that is within the same ethnic group). This also leads to a higher number of autosomal recessive disorders. Each one of us has about 20,000 genes. These genes occur in pairs, one of which comes from the father and one from the mother. Each person carries abnormalities in two or three genes, although in only one of the two copies. Such a person does not get disease because one of the two genes is normal. In consanguineous and endogamous marriages, there are higher chances that the same gene is abnormal in both the husband and the wife, and this leads to autosomal recessive disease in the offspring. We have noticed a higher incidence of autosomal genetic disease among certain communities in India.

How advanced is India, as a country, as far as genetic screening and testing technologies and its access are concerned?

In India, the experts have suggested that newborn screening for hypothyroidism should be initiated as a free national programme. Hypothyroidism is easy to diagnose and cheap to treat. If it is not treated in time, it causes developmental delay in the child. Once the newborn screening programme for hypothyroidism is in place, one can add other disorders to be screened. In the West, every newborn is screened for 50 to 60 disorders.

Another common group which is screened is pregnant women. They are screened for common infectious diseases like syphilis, hepatitis, rubella and CMV, and the urine is screened for the presence of infection or albuminuria. Pregnant women should always be screened for thalassemia, because if both the wife and the husband are carriers of beta thalassemia, the offspring can suffer from thalassemia major, which is a burdensome disease which requires lifelong blood transfusions and has no cure. On an average, the carrier rate for thalassemia is 3-5 % in India, while in some communities the rate is higher.

Much effort and expense go into screening pregnant women for chromosomal disease, which affects almost 1 in 200 births. The commonest of chromosomal disorders is Down syndrome, in which there is an extra chromosome 21. Its incidence is about 1 in 800 births, but the incidence is higher if the mother’s age is more advanced, especially after 38 years. Some doctors feel that it is only the older women who should be screened for Down syndrome in their baby. However, the majority of Down syndrome babies are born to young mothers. So every woman deserves to be offered screening for Down syndrome. The screening is commonly done by using ultrasound studies to look for some markers in the baby that suggest the presence of Down syndrome. Certain biochemical tests are also performed to screen for Down syndrome, such as dual marker test (PAPP-A and free beta HCG) in the first trimester, and Quadruple test (AFP, Estriol, HCG and Inhibin) in the second trimester.

Genetic testing on the other hand refers to testing an individual who has some symptoms. Pre-symptomatic testing can also be done for a person who is at risk for genetic disease, e.g. the child of a person with Huntington disease, Myotonic dystrophy or spinocerebellar ataxia. Offspring of patients with these disorders are at 50% risk of getting the abnormal gene and thus suffering from disease. Such persons should be provided genetic counselling, explaining the implications of pre-symptomatic testing. If the person turns out not to have the abnormal gene, he or she is happy, but if they turn out to have the abnormal gene, they can go into depression.

Most of the genetic screening and testing technologies are available in India. However, some of the tests are expensive for the general population, and need to be subsidized by the government.

How familiar are Indian doctors with these technologies, as genetic services are still not fully integrated into the existing medical education and services?

The awareness about genetic screening and testing is good among doctors in the cities, but those in the periphery have poor knowledge about screening methods and their availability. Earlier, genetic testing was expensive, which limited its use. With the introduction of NextGen sequencing (NGS), the cost of testing has come down drastically. We are fortunate that there are many labs in India offering genetic testing based on NGS, and these are offered at a fraction of the cost in the West.

Many doctors are ill informed about genetic screening and testing. They still harbour the old concept that genetic diseases have no treatment. Therefore, they often feel that there is no need to do genetic testing to make a precise diagnosis. Most doctors and patients in rural areas are not aware that many of the genetic disorders can be treated, while genetic counselling and reproductive counselling can be provided to every person with genetic disease in the family, so that the birth of affected children can be prevented by a variety of methods.

One hopes that the medical establishment realizes the importance of genetics in medical education and services. Genetics has propelled the introduction of “precision medicine”. Here, a person is offered treatment based on his or her genetic constitution, rather than treating everyone in the same way, — what has been called “one size fits all”.  To reap the full benefit of the knowledge of genetic make up of an individual and how it affects their health and disease, the United States has started the one million study called “All of us”, in which the genomes of 1 million people are being sequenced and these people will be followed up to track their medical disorders for realising the full benefits of precision medicine. In the UK, genomes of 100,000 persons are being sequenced, and the genomic constitution will be linked to their medical records to provide information which will drastically change medical practice for the better. The UK NHS has, for the first time, introduced  genomic services. There is an urgent need to start a similar effort in India, because, although the genome of persons in all continents is the same, there are millions of variations that affect the health and diseases and these differ between nations.

Do you think there is an urgent need of establishing medical genetics as an additional department in medical education?

Doctors who regularly read medical journals to update their knowledge realise the importance of genetics in everyday practice. Even the standard medical books are loaded with information about genetics as applied to various diseases. The whole of body functions are controlled by genes, so it is not surprising that all diseases have a genetic component. Only some have more than the others. For example, thalassemia is a single gene disorder and is only affected by the environment in a minor way. However, disorderssuch as hypertension, diabetes mellitus and coronary artery disease arise due to interplay of environmental and genetic factors. In the field of cancer, the entire treatment is now-a-days guided by the genetic mutations in tumour tissue.

India has already started feeling the tremendous scarcity of medical geneticists and genetic counsellors. Only a handful of institutions are providing training in medical genetics (Sanjay Gandhi Postgraduate Institute in Lucknow, All India Institute of Medical Sciences in Delhi, Postgraduate Institute in Chandigarh, Manipal University in Mangalore). The total medical geneticists in the country may be about 100, which is totally inadequate for a country the size of India. The Department of Biotechnology, Government of India, realizing the value of genetics in medicine, sponsored a national postgraduate course in medical genetics involving three institutions (Sir Ganga Ram Hospital in Delhi, Nizam’s Institute in Hyderabad and National Institute of Biomedical Genomics, Kalyani). More such training programs need to be started.

The government has now proposed mandatory genetic screening of pregnant women for thalassemia and sickle cell anaemia. But, which are the other critical disorders that deserves such policy intervention and priority attention in the country? 

I do not know of any circular by the Ministry of Health to make screening for thalassemia mandatory in the country. I learnt that in Karnataka, the Health department has issued instructions to the doctors in Government hospitals to do this. How effective this order will be remains to be seen. Generally, international organizations such as the WHO and Thalassemia Federation have desisted from making any screening mandatory, except newborn screening. But certain countries have done so, notably Iran, the UAE and Saudi Arabia. It is difficult to enforce such an order, because first one has to provide the facility for screening and diagnosis. We tell all obstetricians to screen pregnant women under their care for thalassemia at first contact. Many do not do this, as they only ask for haemoglobin estimation, which cannot tell us about the carrier status for thalassemia. If the government provides the proper facilities for screening and then confirmatory diagnosis of thalassemia and sickle cell disease as a free or subsidized service, this will have an immediate impact on the number of affected children born with thalassemia major and sickle cell diseases in India.  But this is not an easy task for a country as large as India with states in different stages of development.

As I mentioned earlier, almost all obstetricians screen women during pregnancy for the common infections. Many screen the women under their care for thalassemia. This is good practice and the earlier obstetricians make this a routine practice, the better it would be for the country. Every woman should be asked a family history of genetic disease, and if this is present, tests should be done to assess the risk to the baby being born with that disease. Many preventive tests can be carried out, and these are available in India, although one could do with more such facilities. Ideally, any woman who has someone in her family suffering from genetic disease should tell her obstetrician about this at the earliest. The best way is of course, if she consults and tells the obstetrician before the pregnancy, which allows enough time to investigate whether the lady is at risk. If information about this becomes available at a later stage of pregnancy, there may not be enough time to complete the studies.

The genetics group at Sir Ganga Ram Hospital counsels about 5,000 people per year. Based on this experience, as well on the results of studies on carrier screening among healthy persons that we have carried out, we would recommend the following genetic disorders to be commonly screened in India: spinal muscular atrophy (SMA), congenital adrenal hyperplasia (CAH), Duchenne muscular dystrophy (DMD), fragile X syndrome, cystic fibrosis and some genes for deafness. A couple of vendors are providing carrier screening tests, but one company screens for 100 diseases as well as SMA, DMD and CAH in both partners at a price of Rs. 25,000. This is remarkably cheap, and one hopes more couples would opt for this test.