Genomics of rare genetic diseases—experiences from India

Abstract

Home to a culturally heterogeneous population, India is also a melting pot of genetic diversity. The population architecture characterized by multiple endogamous groups with specific marriage patterns, including the widely prevalent practice of consanguinity, not only makes the Indian population distinct from rest of the world but also provides a unique advantage and niche to understand genetic diseases. Centuries of genetic isolation of population groups have amplified the founder effects, contributing to high prevalence of recessive alleles, which translates into genetic diseases, including rare genetic diseases in India. Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 240 clinician/scientist collaborators across 70 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. In addition to GUaRDIAN, several genomic investigations for diseased and healthy population are being undertaken in the country to solve the rare disease dilemma. In summary, rare diseases contribute to a significant disease burden in India. Genomics-based solutions can enable accelerated diagnosis and management of rare diseases. We discuss how a collaborative research initiative such as GUaRDIAN can provide a nation-wide framework to cater to the rare disease community of India.

IndiGenomes: a comprehensive resource of genetic variants from over 1000 Indian genomes

“…These rare/unique variations amplify as founder mutations within specific endogamous populations, which in due course translates to population specific genetic diseases. It is estimated that ∼70 million people in India are affected by genetic diseases with about 64 out of 1000 live births carrying disorders such as primary immunodeficiencies, lysosomal storage disorders, mitochondrial diseases, cardiac disorders and muscle-related disorders ( 5 ). The government of India is now focusing on effective cataloging of the genomic variants specific for the Indian population so as to create a blueprint for identification of disease epidemiology, population-specific variants and pharmacogenomic markers ultimately leading to the development of effective therapies for treating genetic disorders ( https://pib.gov.in/PressReleseDetailm.aspx?PRID=1605509 ).…”

“…This has resulted in high prevalence of recessive alleles in the Indian population. In the absence of large-scale whole genome studies from India, these sub-population-specific genetic variants are also not adequately captured and catalogued in global medical literature ( 5 ).…”

A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early‐onset monogenic disorders in Indians

“…The high burden of monogenic disorders is well described in the Indian population (Kaur & Singh, 2010; Sachdeva et al, 2012; Singh et al, 2010; Sivasubbu & Scaria, 2019; Venugopal et al, 2018). However, the incidence and prevalence and consequently the carrier frequencies for most disorders remain unknown.…”

“…Carrier screening was mostly carried out in couples with a previous history of putative recessive disease in the deceased offspring and nonavailability of samples from the proband/s. Globally, thalassemia and structural hemoglobinopathies are the commonest monogenic disorders and India too has a huge burden of these conditions (Colah et al, 2017; Sivasubbu & Scaria, 2019; Williams & Weatherall, 2012). Patients with β thalassemia and sickle cell disease in India are estimated to be 100,000 and 150,000 respectively and the reported average prevalence of carriers for β thalassemia is 3%–4% (Colah et al, 2017) whereas sickle cell disease was observed with a carrier frequency ranging from ~1% to 40% in specific subpopulations in India (Hockham et al, 2018).…”

Ophthalmic genetics practice and research in India: Vision in 2020

“…Genomic sequencing consortia funded by the government such as GUaRDIAN, (GUaRDIAN Consortium, Sivasubbu, & Scaria, 2019), Indian Genetic Disease Database (IGDD) (Pradhan et al, 2011) are helping us understand the population genetics. Specifically, IGDD website http://www.igdd.iicb.res.in/home.htm enlists the specific mutations found in the Indian population.…”