Screening for rare genetic disorders becomes easier


The Institute of Genomics and Integrative Biology has the data of all disease-causing mitochondrial mutations and the frequency of every single disease-causing mutation in the global population.

Fast and accurate diagnosis of disease-causing mitochondrial genetic mutations is now possible thanks to automation of the entire process of data analysis and interpretation by a team of researchers at the Delhi-based CSIR Institute of Genomics and Integrative Biology.

The comprehensive pipeline developed by a team led by Dr. Sridhar Sivasubbu and Dr. Vinod Scaria of IGIB includes methodologies to sequence mitochondrial genome using next generation sequencing and a software to appropriately analyse and interpret the data at a point-of-click.

Mitochondria, the powerhouses of the cell, are unique in several ways. A cell can have multiple mitochondriae, with each mitochondriae differing from one another by a few variations.  This phenomenon is known as heteroplasmy. Heteroplasmy can vary between cells of the same tissue, organ, individual or even between individuals of the same family.

Though heteroplasmic mutations implicated in mitochondrial diseases are seen even in healthy individuals, the reason why they do not manifest as disease is due to low-frequency of heteroplasmy, usually less than 10 per cent. “Nearly 20 per cent of normal individuals harbour heteroplasmic mutations reported to be implicated in mitochondrial diseases but the frequency is less than 10 per cent,” says Dr. Scaria.

The mutations could also be acquired during cell division. While all cells will carry the mutations associated with disease when it is inherited, cells in different tissues may have different mutations when it is acquired.

Also, compared with nuclear genome, the mitochondrial DNA has a 5-10 times greater rate of mutation than nuclear DNA.  “So it is not surprising that mitochondrial disorders are one of the commonest rare genetic disorders, with an incidence of approximately 1 in every 5,000 births globally,” says Dr. Scaria.

The entire process of data analysis and interpretation has been automated.

Though many hospitals now have the Next Generation Sequencing, doctors do have the expertise to do the entire process of seeing where the mutations are and interpret if the mutations so seen cause disease or not. Also, the frequency of heteroplasmic mutations needs to be known.  Many of the so-called mutations are common in the population but at a lower heteroplasmic frequency. “If the frequency is more in the population then the mutation is probably not a disease-causing one,” Dr. Scaria says.

“We have attempted to close this gap by automation of the entire process of data analysis and interpretation,” he says. First the mitochondrial genome is sequenced using next generation sequencing. To make interpretation possible, the raw data is overlaid on the mitochondria genome and the positions where the variations are present are noted and the frequency of the variation in the sample is also recorded. The disease caused by each mutation is checked with the data bank and compared with the population frequency. Since IGIB has the data of all disease-causing mutations and the frequency of every single disease-causing mutation in the global population, comparing the frequency of the sample with the population can be carried out automatically.

“The commercial application of the knowledge base would enable fast and accurate diagnosis of mitochondrial genetic mutations with implications in clinical diagnosis, prenatal testing and carrier screening,” he says.

This technology has been licensed to the Bengaluru-based Eurofins Clinical Genetics India Pvt Ltd. to enable fast and accurate diagnosis, screening at clinical turnaround times and research into mitochondrial diseases. The service is presently available in India as MitoSure.

The company has been testing samples since mid-April. “We have so far tested 25 families,” says Dr. Surendra Chikara, Executive Director of Eurofins. The cost per test ranges from Rs.15,000-20,000 and has a turnaround time of two weeks. “We will soon be starting screening campaigns for families with known history of disease-causing mitochondrial genetic mutations. This will help the family to know the female members’ carrier status,” Dr. Chikara says. In this case, the identified mutation alone is screened and cost Rs.5,000 per person.