GUaRDIAN – Guard you from Rare Genetic Disorders

Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN), a research consortium to provide a nation-wide framework to provide genomics-based solutions to enable accelerated diagnosis and management of rare diseases in India.

Aswini B | 07 October 2019

India is a land of genetically and culturally diverse population. The practice of endogamy (marriage within a specific tribe or similar social unit) followed by vast Indian populations has led to genetic isolation of a particular population and accumulation of genetic mutations. This translates into rare genetic diseases. There is no proper definition to describe rare diseases in India. Indian Council of Medical Research (ICMR) defines a disease as rare if it affects <1 in 2500 individuals and The Organization for Rare Diseases India (ORDI) defines it as 1 in 5000. India, being the second populous country in the world, has a huge population and rare genetic disorders are not really rare, but they translate into a huge disease burden. According to the Foundation for Research on Rare Diseases and Disorders, about 70 million people are estimated to be affected by rare diseases. Around 64 of 1000 live births in India carry a birth defect and 1 in 20 children suffer from some form of genetic diseases. Also, there is a lack of a centralized clinical registry of patients with rare genetic diseases in India and hence, there is no estimation of the prevalence of rare genetic diseases. It is being a great challenge to be able to diagnose and treat rare disease patients.

Genomics-based approaches have been demonstrated to speed up the diagnosis of rare genetic diseases and reduce the socio-economic burden. Hence, to address the challenges, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi has started a unique research initiative to solve and understand rare diseases - The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN). The consortium aims in using genomics as a tool for systematic characterization and diagnosis of rare genetic diseases in India and to establish a collaborative framework in health care planning, implementation, and delivery. Within the GUaRDIAN framework, whole genome or exome datasets of the rare disease patients are generated and analyzed computationally to identify the causal and pathogenic variations in genes. It has collaborated with hospitals and major tertiary care centres across India and includes over 240 clinicians/researchers, from 70 clinical/research centres.

The program maintains a clinical registry by collecting detailed clinical information of the patient and family members. The registry will help to identify the disease burden of rare diseases in India and will provide insights into the common and rare genetic variants in different sub-population.

The outcome of GUaRDIAN is being translated into community services through a suitable platform providing low-cost diagnostic assays. There are many success stories of GUaRDIAN. As a case in study, six children of a Muslim family (belonging to the Nalband community), were suspected to be affected by leukodystrophy. Whole exome sequencing of the affected and unaffected individuals of the family helped in diagnosing the patients to harbor a rare mutation in megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) gene, which leads to megalencephalic leukoencephalopathy. They screened 83 more members from the same community and found 9 affected individuals and 24 carriers. The community comprises of over 5000 individuals and is distributed across north India and Pakistan. Consanguineous marriages are common in the community. Hence, to aid the entire community, the consortium has designed a polymerase chain reaction (PCR) - based assay for the particular mutation in MLC1 for carrier status determination and prenatal screening, at an affordable cost.

Similarly, GUaRDIAN has made a significant contribution to another rare disease Epidermolysis bullosa (EB), a skin-blistering disease. It has taken a few international initiatives where they derive the pharmacogenomic landscape in Malays and Qatari populations. They have identified the pharmacogenetic variants in dihydropyrimidine dehydrogenase (DPYD) gene (determines the metabolism of antineoplastic drug 5- fluorouracil) in south-east Asian countries, identified genetic variants of Arab, Middle East, and North African populations. GUaRDIAN has also set up a systematic pipeline for next-generation sequencing of the mitochondrial genome for clinical applications - The mit-o-matic. They have prepared a handbook called ‘Exome Sequence Analysis and Interpretation for Clinicians'.

In Short, rare diseases contribute to a significant disease burden in India and genomics-based solutions can enable speedy diagnosis and management of the diseases. The GUaRDIAN outreach program has taken a small step in providing a nation-wide framework to manage and provide health and economic benefits to families with rare genetic diseases.


This work was published in Human Genomics in September 2019. The article is available online at https://doi.org/10.1186/s40246-019-0215-5