Medical genetics and genomic medicine in India: current status and opportunities ahead

Medical genetics and genomic medicine in India: current status and opportunities ahead. India is the sixth largest country of the world in size and with a population 1. 21 billion (http: //www. censusindia. gov. in) has the distinction of being the second most populous country of the world, housing 17. 5% of all humans (http: //www. prb. org). It is part of the Indian subcontinent that is comprised of the surrounding countries of Pakistan, Bangladesh, Srilanka, Nepal, and China with whom it shares common cultural and anthropological roots. The southern part of India is the Indian peninsula surrounded by the Indian Ocean, the Bay of Bengal, and the Arabian Sea (Fig. 1). The Indian subcontinent has been the seat of some of the oldest civilizations of the world with the earliest historically documented remains dating back to as early as 70, 000 years. This region is believed to have been initially habituated 55, 000–80, 000 years back by migration from the African continent as indicated by mitochondrial and Y chromosome DNA genotypes (Majumdar 2010; Tamang et al. 2012). Subsequently, multiple events of migration and invasions from northwestern and eastern sides led to population admixture giving rise to highly heterogeneous population groups in this country. Presently, there are believed to be four main ethno-racial groups- the Caucasoids, Australoids, Mongoloids, and Negritos- in India. The Caucasoids inhabit the northern and northwestern part and speak the Indo-Aryan langauages, the Australoids the southern part and speak the Dravidian languages and the Mongoloids the northeastern part of the country and speak the Tibeto-Burman languages. The Negritos are confined to the Andaman Narang et al. 2010; Tamang et al. 2012). Genetic studies for classifying the population into subgroups and identifying the origins have been at the best incomplete due to the vast population and extreme complexity. This poses challenges for genetics and genomic medicine research. In recent years, the Indian Genome variation consortium project has studied polymorphisms in 900 genes from 55 different population groups of India and these variations have been catalogued in the Indian Genome Variation browser. This forms an important database for design of further studies of multifactorial as well as single gene disorders (Narang et al. 2010). The geographical Majumdar 2010; Tamang et al. 2012; Juyal et al. 2014). Consanguinity is as high as 20–30% in some specific populations, indicating the possibility of clusters of specific diseases and founder mutations (Bittles 2002; Juyal et al. 2014). Although almost all known genetic disorders have been reported in India, and regional distribution for many conditions historically known, prevalence data and the mutation profiles are not well known for the majority. The underlying population genetic heterogeneity poses significant challenges in this regard. In addition to the complexity and the magnitude of population, the presence of disparity in economical and infrastructural resources at the level of population subgroups as well as individuals further complicates the health care delivery and access to genetic services (Balarajan et al. 2011). The health services in India are available as a public service which is provided by the Government of India under the Ministry of Health and Family Welfare as well as a private service which is provided by various corporate organizations in addition to individual practices (Balarajan et al. 2011, http: //www. mohfw. nic. in). India spends 1. 2% of its GDP on health, and provides completely free or highly subsidized health services to the economically deprived groups through the public health system (Balarajan et al. 2011). This system consists of tertiary level hospitals in the larger cities, secondary level hospitals which are the district and taluka hospitals and the primary health centers for both the urban and rural population. The tertiary level hospitals are usually allied to a medical school and are involved in training of doctors and other medical personnel. A large proportion of clinical as well basic scientific research is conducted under the aegis of these institutions many of which like the All India Institute of Medical Sciences, New Delhi; Post Graduate Institute of Medical Education Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, etc. are recognized for clinical excellence as well as research contributions (http: //www. mohfw. nic. in). The planning of health service delivery, training of personnel, and allocation of budget is governed by the Ministry of Health Jindal 2014). Hence, the private health services cater to the health needs of the majority of the population (Balarajan et al. 2011; Jindal 2014). This system is highly heterogeneous and its pattern differs across different regions of the country. Larger urban areas have super-specialty hospitals governed by various corporate bodies and these are primarily accessed by the economically privileged class. Many of them offer state of the art medical care and are popular destinations for medical tourism from across the world. However, smaller nursing home practices and individual practices are responsible for providing health care to the majority of Indians both in rural and urban areas. These in turn are varied in their level of care depending on the expertise of the doctors and the infrastructure availability (Balarajan et al. 2011; Jindal 2014). Most medical care is funded by individuals themselves and in some cases by the employer while private medical insurance is taking roots in India (Balarajan et al. 2011; Jindal 2014). The quality regulation of medical practice is primarily the responsibility of the Medical Council of India (MCI) which lays down guidelines for both the training of the doctors as well as their professional conduct (http: //www. mciinidia. org). The National Board of Examinations is another governing body which is involved in training of doctors in addition to MCI approved courses in medical institutions (http: //www. natboard. edu. in). With decreasing trend of infant mortality rates in India, genetic disorders are emerging as an important group of medical ailments requiring attention at a priority level. Genetic services in India can be dated back to the commencement of small genetic units in few premier cities like Delhi, Lucknow, Bangalore, Mumbai, and Pune as multicentric research programs for prevention of neural tube defects, etiological diagnosis of mental retardation and high-resolution cytogenetics funded by the Indian Council of Medical Research (ICMR) in the late 1980s (www. icmr. nic. in). Clinical genetics gained momentum as a consequence of pioneering efforts of senior geneticists like SS Agarwal, IC Verma, M Phadke, and IM Thomas. These services have progressively expanded over the last 30 years and as many as 40 trained Medical and Clinical geneticists practice all over the country at present. Many of the earlier geneticists have received part or whole of their training abroad, but the establishment of the Medical Genetics residency program as early as 27 years back at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow has been the primary training source for the newer generation of geneticists. Medical genetics services are presently available in 13 different premier cities of New Delhi, Lucknow, Vellore, Chandigarh, Hyderabad, Bangalore, Pune, Ahmedabad, Kochi, Trivandrum, Chennai, Manipal, and Mumbai as a separate department or units under the pediatrics department. In addition, many trained geneticists practice clinical genetics as part of their pediatric practice. The majority of the Medical Genetics outpatient services in the larger centers cater to an average of 20–40 patients on a daily basis. The cases include pediatric and adults, with antenatal patients comprising a significant proportion at many centers. Many geneticists and fetal ultrasonographers provide genetic sonogram and prenatal diagnosis services as part of their practice. Prenatal diagnosis has contributed to the popularity of medical genetics amongst obstetric practitioners. The growing significance of molecular genetics and cytogenetics in diagnosis as well as management of various cancers has also led to expansion of genetic diagnostic and counseling services in the country. As no trained genetic counselors are existent in the country, the medical geneticists also provide genetic counseling services to their patients. Hence, the work profile of a medical geneticist in India is varied and broad dependent upon the needs of the population, availability of other trained personnel and the kind of organization he/she is part of. Many of the geneticists take care of patients with dysmorphology, genetic metabolic disorders, disorders of sexual differentiation and development, neurodegenerative disorders, skeletal disorders, cancer genetics, adult onset disorders, etc. In addition, most medical geneticists are actively involved in diagnostic and research laboratory work, though some function primarily as clinical geneticists. Diagnostic laboratory facilities are available both as part of an integrated medical genetics department/unit or as an independent facility. The integrated laboratories are supervised by laboratory geneticists or medical geneticists whereas the independent facilities are primarily supervised by laboratory geneticists. Cytogenetics, molecular genetics and biochemical genetics diagnostic tests are all available in most of these facilities. Some laboratory facilities have developed as part of other specialties like anatomy, biochemistry, hematology, and pathology in medical institutions. Recent years have seen marked expansion of private laboratories in the field of genetic diagnostic services. Availability of cytogenetic microarray and next generation based testing has brought the diagnostics to the state of art level but also needs responsible and knowledgeable geneticists for interpretation and to carry out the responsibility of appropriate pretest and post-test counseling. However, as is true for the clinical genetic services, most of the laboratory services are present in a few cities of the country in selective premier institutions. Patients from the rural and suburban areas of the country need to travel long distances to access both clinical and laboratory genetic services. The launch of the website is an important milestone in the medical genetics in India. The website has been supported by Indian Council of Medical Research and is the result of council's funding support to many investigators working on various monogenic disorders. It provides a catalogue of genetic laboratories, tests and genetic counseling centers for use by clinicians as well as patients (http: //www. geneticsindia. org). There is no provision for genetic evaluation for the majority of the population and no national public health program is currently functional for carrier or newborn screening for genetic disorders. Population based carrier screening for beta thalassemia which was initiated as part of scientific projects is currently being started as government supported program in some states and has been recommended for countrywide implementation (Verma et al. 2011). Newborn screening has also been done on research basis and recently has commenced as a pilot program in one of the states (Kerala) of the country (Agarwal et al. 2015). Acceptance and performance of these programs and improved budgetary allocations may lead to possible expansion to nationwide screening in the new future. A birth defects registry has also been initiated in the last few years by a nongovernment organization but nationwide coverage has not been possible due to inadequate interinstitutional communication (http: //www. fcrf. org. in/bdriₐbus. asp). Regulation of genetic diagnostic services is presently governed by the ICMR's ethics guidelines for biomedical research as no separate standards are available for the same. Prenatal diagnostic services are more stringently regulated by the Preconception and Prenatal Diagnostics Techniques (Prohibition of Sex Section) Act, 1994, which is primarily intended to curb the practice of prenatal sex determination for sex selection by female feticide (http: //pndt. gov. in). This act outlines the requisite training of personnel and laboratory specifications for a genetics laboratory performing prenatal diagnosis. In addition this law also provides guidelines for a genetic counseling and prenatal diagnosis all of which an important of medical genetic services in India. However, separate laboratory standards are for genetic diagnostic laboratories as presently most laboratories are guidelines or appropriate by individual quality which has for prenatal diagnosis practice in India is the Act, which into to the availability of prenatal testing with the primary to This act the of as This challenges for management and counseling of various late genetic and birth defects, and has led to of an recently et al. all known reported genetic disorders are in India. Medical geneticists as well as clinicians from other have been cases in the medical their However, the data has been from institutions or individuals and nationwide prevalence of most disorders is not thalassemia is the most common genetic and has a carrier of with some population groups carrier rates et al. Most of the genetic centers in India initiated their molecular diagnostic laboratories by genetic testing of beta thalassemia and data of mutation from various states and population groups is available et al. et al. et al. et al. et al. 2011). The genetic conditions like and have prevalence and carrier rates to genetic disorders like disorders, and many have been reported in large from all of the country. from small newborn screening reports and of clinicians that all of are seen in India et al. et al. and 2002; et al. 2011; and diagnosis has been of to many as is by a of reports of and new of known in pediatrics of India and and et al. et al. and et al. et al. et al. of of Indian patients has been of to clinicians across the world et al. 2012). Many new have been reported by Indian and have been in and the (Verma et al. et al. et al. et al. et al. et al. 2002; and and et al. and et et al. 1). However, due to cases to the have not been in identifying With the genomic these from are a for gene et al. 2014). The high rates of and practice of has been to lead to the high prevalence of conditions as well as founder mutations in specific population Although there is no data to population level high prevalence of disorders in with high Phadke, that is times more common in with disorders as to the most common beta thalassemia of microarray to regions of and genes in these regions is a which can be in the et al. 2015). Some conditions to be common have been with a founder mutation in the from India, forms of of and from a specific in South India et al. et al. 2010; et al. 2011, 2012; et al. 2011; et al. 2012; et al. 2012; et al. et al. 2015). However, the available data on monogenic and metabolic disorders from India though only of the as a large population not have access to the clinical genetics services due to and of genetic centers. and common have also been in large In recent years, with availability of microarray are also being et al. 2014). to many centers use dependent for diagnosis of and common et al. 2014). defects are common in the Indian population, with various like in addition to genetic (Agarwal et al. et al. and et al. The of Medical geneticists in antenatal as well as has led to of known as well as in many cases and cancers and cancer monogenic have been also an important part of to a clinical genetics for Research and Education in in Mumbai has the largest cancer genetics and provides molecular diagnosis for many monogenic cancer Many other centers have research and clinical services in the field of cancer genetics et al. et al. India of the Genome et al. et al. 2014). Genetic studies and research in disorders by many centers in India have been et al. 2008; et al. et al. 2012). programs in Medical Genetics are available currently in four centers in the country. these a residency program at Sanjay Gandhi Post Graduate Institute of Medical Lucknow has been the oldest one currently in its and has the distinction of being the only program in an under the Government of India. programs are courses of years in private institutions. The of Medical Genetics at Lucknow also a long program for It is at training medical and private in basic genetics an to common genetic diagnostics and genetic counseling. This is a popular program and is supported by Indian Council of Medical Research for more than years. Many other centers have been and in genetics and most of the medical have improved the coverage of genetics in their scientific Medical Council of India has been taking to genetics in and medical there have been in recent years commencement of programs for laboratory geneticists at the for DNA and under the aegis of for Indian of Medical A in genetic counseling started recently in Medical Genetics department of Medical is the in trained genetic counselors trained in clinical a residency program under the National Board of Examinations is to in centers in different of the country. The for Indian of Medical Genetics has into the and has brought the Medical and Clinical geneticists across the country. The has been of clinical and research data different centers. The also has a Genetic cases and in the field are with an to out to doctors from other The Indian of Genetics has also been in basic scientific research in genetics through its and an the Indian of Genetics institutions with integrated medical genetics centers as well as institutions to scientific research have been in pioneering genetic and genomic research in India. The research to monogenic disorders has been under the of primarily medical geneticists whereas research to cancer genetics, multifactorial disorders and population genetics has been out primarily by The research is funded by individual institutions as or by national organizations like the Indian Council of Medical Research, of of and and Council for and The premier institutions to scientific research in the field of genetics have been the for et al. 2011, 2012; et al. 2011; et al. 2012; et al. 2012; et al. 2012; et al. et al. et al. Verma, In recent Medical geneticists have started in of genetic disorders et al. Agarwal, Phadke, A in with mutations population population data and mutation mutation in some support groups a important in the care of patients with genetic disorders in India almost no support in the public health care system for these and conditions Many of these conditions and like disorders and various of have highly The support groups for and thalassemia patients have been in many years and have been in state for these disorders in many regions of India support groups for and disorders are roots in the country and have been working and for subsidized and state support for these conditions for diseases has recently been et al. 2014). with availability of medical the support are for these patients and their and are that appropriate attention from the this not to an all of the and present of medical genetics in it is an to the and the current The over last have brought state of art molecular diagnostics to India and with clinical in and metabolic of medical genetics has been in India the to the patients with genetic disorders and their However, though a has been the research in the of genetic disorders in the areas of and new Research in gene and is almost Research and in these areas and a long in the new available to Indian patients at The genetic the vast the high rates of all India as a in the field of A large of clinical remains for research. in the field and availability of state of the art clinical and diagnostic the of geneticists and laboratories are to cater to the population of India. health budget of the health and the of genetic of genetics in medical and amongst medical from other are important for this programs like newborn thalassemia prevention and screening need to be by government than current pattern of private prevalence of and their is for of group and of in implementation of appropriate screening and management programs for patients. Medical Council of India needs to take the of modern genetics at all of medical that the generation of medical is for the of molecular There is a need for improved clinical geneticists and basic that the clinical can be research numerous reports of new from India, there has been no in the of gene high rates of in with genetic disorders, which are for Recent of in with microarray can gene in small as well et al. et al. With the of gene by the world is to genes for all monogenic disorders and India be able to to this last of gene like to various organizations like the Indian Council of Medical Research, of of and Council for and Research, etc. for the funding of various research and programs in the field of Genetics which have contributed to the of Medical Genetics and in India.