REVIEW OFFICIAL JOURNAL Clinical Applications and Implications of Common and Founder Mutations in Indian Subpopulations www.hgvs.org Arunkanth Ankala,1∗ † Parag M. Tamhankar,2 † C. Alexander Valencia,3,4 Krishna K. Rayam,5 Manisha M. Kumar,5 and Madhuri R. Hegde1 1Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia; 2ICMR Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India; 3Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 4Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; 5Department of Biosciences, CMR Institute of Management Studies, Bangalore, Karnataka, India Communicated by Arupa Ganguly Received 24 October 2013; accepted revised manuscript 16 September 2014. Published online 27 November 2014 in Wiley Online Library (www.wiley.com/humanmutation). DOI: 10.1002/humu.22704 that include a lack of widespread awareness about genetic disorders in the general population and the scarcity of specialized medical ABSTRACT: South Asian Indians represent a sixth of the world’s population and are a racially, geographically, and professionals and affordable genetic tests. Seeking a molecular di- genetically diverse people. Their unique anthropological agnosis and understanding the risk estimates are critical to making structure, prevailing caste system, and ancient religious sound reproductive choices, especially in families with an affected practices have all impacted the genetic composition of most individual. Adding to this adversity is the absence of a properly func- of the current-day Indian population. With the evolving tioning social health care system and insufficient encouragement socio-religious and economic activities of the subsects and of individual health insurance by the government. Consequently, castes, endogamous and consanguineous marriages became even interested and informed individuals cannot afford to seek a a commonplace. Consequently, the frequency of founder molecular diagnosis or genetic services. The World Health Organi- mutations and the burden of heritable genetic disorders zation (WHO) has appropriately stressed the need for early diag- rose significantly. Specifically, the incidence of certain nosis, prevention, and management of genetic disorders in devel- autosomal-recessive disorders is relatively high in select oping countries and released detailed guidelines [Christianson and Indian subpopulations and communities that share com- Modell, 2004]. However, to practice these guidelines and reduce mon recent ancestry. Although today clinical genetics and disease burden, there must be efforts to improvise and make diag- molecular diagnostic services are making inroads in India, nostic tests affordable. In a vast country like India, where the disease the high costs associated with the technology and the tests burden is tremendous and resources are limited, low-cost diagnostic often keep patients from an exact molecular diagnosis, tests that target specific common mutations or founder mutations in making more customized and tailored tests, such as those select communities or subpopulations hold significance. Rightly so, interrogating the most common and founder mutations studies aimed at identifying many more common as well as founder or those that cater to select sects within the population, mutations are expected to further the development of low-cost and highly attractive. These tests offer a quick first-hand af- targeted assays, such as those discussed here. Here, we make an effort fordable diagnostic and carrier screening tool. Here, we to outline the significance of such studies by providing examples of provide a comprehensive catalog of known common mu- recently identified founder mutations. We also discuss the common tations and founder mutations in the Indian population genetic disorders in India and provide a thorough catalog of com- and discuss them from a molecular, clinical, and historical mon and founder mutations, along with their clinical applications perspective. and significance. Hum Mutat 36:1–10, 2015. C 2014 Wiley Periodicals, Inc. KEY WORDS: founder mutations; clinical genetics; India; Current State of Clinical Genetics Services in India common variants; molecular testing With the efforts of national agencies and funding bodies, such as the Indian Council of Medical Research (ICMR) founded by the Ministry of Health and Family Welfare of India, the pace of research and expanded clinical services in genetics has picked up Background in India in recent years. ICMR has institutionalized the Genetic Rough estimates are that more than 50 million individuals in Research Center (GRC) to regulate genetic research in the coun- India are affected with single-gene disorders (monogenic disorders) try and offer clinical services to diagnose genetic disorders. In ad- [Singh et al., 2010]. This number is expected to rise due to factors dition to the national agencies, private organizations such as the Organization for Rare Diseases India (ORDI) are making signifi- cant efforts to extend genetic services and address the challenges Additional Supporting Information may be found in the online version of this article. and concerns of rare diseases in India [Rajasimha et al., 2014]. †These authors contributed equally to the manuscript. Currently, there are only 68 accredited centers in India offering ge- ∗Correspondence to: Arunkanth Ankala, PhD, Department of Human Genetics, netic testing and/or counseling services (http://geneticsindia.org); Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. E-mail: most of these clinical laboratories only offer diagnostic assays that [email protected] target either a single more recurrent mutation or a small set of C 2014 WILEY PERIODICALS, INC. Table 1. Founder Mutations in Agrawals Mutation Allele Disease Gene OMIM# Mutation frequency (%) count Region/sect Reference Hallervorden–Spatz syndrome PANK2 606157 c.216dupA Founder (58.3) 7/12 Agrawals Aggarwal et al. (2010) ∗ Heme oxygenase 1 deficiency HMOX1 141250 c.130C>T (p.R44 ) Founder (100) 2/2a Agrawals Radhakrishnan et al. (2011) LGMD2A CAPN3 114240 c.2338G>C (p.D780H) Founder (50) 9/18 Agarwals Ankala et al. (2013) LGMD2A CAPN3 114240 c.2051–1G>T Founder (50) 9/18 Agarwals Ankala et al. (2013) Megalencephalic leukodystrophy MLC1 605908 c.135dupC Founder (100) 62/62 Agarwals of Gorospe et al. (2004) with cysts North India aFounder effect of the mutation was established by haplotype studies and detection of the mutation in multiple affected individuals (personal communication by IC Verma). Allele count, number of alleles with mutation/number of alleles tested. well-established mutations within a specific gene. Moreover, there disorders in Indian populations (Table 1). In addition to founder ef- are only two established genetic counseling programs in India, and fects, cultural and religious practices in India are such that intracom- as few as 25 trained (formally or informally) genetic counselors munal and intracaste arranged marriages are frequent, further rais- across the length and breadth of the country [Elackatt, 2013]. These ing the risk of carriers of the same mutation or disease being united. limitations call into serious question the amount of counseling (if Identifying and cataloging founder mutations in Indian populations any) and the testing options available or offered to a couple making will allow for carrier and prenatal testing options, regardless of fam- reproductive decisions. ily history, holding out the promise of controlling disease burden. Disease Burden and Control Measures in Practice in India Founder Mutations and Their Contribution to Disease While most developed countries have an established and closely Prevalence monitored newborn screening program (NSP) to identify new- In general, founder mutations are defined as recurrent mutations borns with selected genetic disorders (e.g., endocrinopathies and observed on a single haplotype background in a particular popula- metabolic disorders) and provide early intervention, there is no tion. They help us understand the evolutionary aspects of human such program in place yet in India. With several pilot newborn disease [Drayna, 2005]. As a special category of mutation, founder screening studies reporting a high incidence of a selected group of mutations enable scientists to trace the ancestry, migration, and disorders, the overall burden on the nation is becoming clear, and growth of specific human populations over time [Vernengo et al., there is growing urgency to implement a national NSP [Kapoor 2011]. Apart from these anthropological traits, founder mutations et al., 2013]. Even though a NSP allows for the early identification also hold medical significance in that they cause the high frequencies of and intervention for a disease in affected individuals, the cost of recessive diseases in certain populations, such as the AJs men- and discomfort of continuous treatment and management are sig- tioned earlier [Slatkin, 2004], the Helsinki population of Finland nificant, both for an individual’s family and the nation. A second [Lao et al., 2008], as well as several Indian subpopulations, includ- and more broadly applicable (to more diseases) protocol that com- ing the Agrawal community [Ankala et al., 2013]. In fact, founder plements the NSP effort and helps meet the objective of reducing mutations are believed to contribute more to the burden of reces- disease burden is the