Page 19 - Biennial Report 2018-20 Jun 2021

GENOMICS APPROACHES FOR RARE GENETIC DISEASE DIAGNOSIS

Over the years, exome sequencing has been utilized as a major technique for identifying variants
that cause rare genetic diseases. As mentioned in other sections of this report, at IGIB, exome
sequencing has been successfully used to identify causative mutations in a variety of genetic
diseases. Patient cohorts have been subjected to whole exome sequencing at IGIB, in
collaboration with our clinical partners. These included patient cohorts suffering from
Genodermatosis, rare cardiac channelopathies and nephrotic syndrome, among others. Based
on these studies, it was observed that exome sequencing could successfully identify causal
mutations in about 40% to 70% of the patients depending on the disease being investigated. It
was clear from the data that exome sequencing could identify causal mutations in a subset of
patients. For the remaining patients, a whole genome-based approach was proposed, which can
be valuable for diagnosis of rare genetic diseases.

The main objective of the RAREGEN program is to provide the technological basis, clinical
outreach and implementation of whole genome sequencing-based healthcare solutions and
molecular diagnostic assays through genomic medicine. With the growing impact of genomic
medicine in India, such a program is expected to change the course of diagnosis and touch the
lives of patients, their families and society in the specific area of rare genetic diseases. This would
be achieved through building a systematic approach focusing on enabling the smooth adoption
of the whole genome/ exome/ targeted panel sequencing in clinical settings, considering the
throughputs required and automation for clinical / commercial applications. Whole genome
sequencing approaches will be undertaken for diagnosis and functional validation of variants in
genetic diseases in India. Specifically, an affordable molecular genetic assay for diagnosis of
Wilson's disease (WD) in India will be developed by the group under the leadership of Dr.
Binukumar B.K.

Over 400 samples were received
from clinical collaborators in the
guardian network across India.
Only samples that had informed
consent, a provisional diagnosis
and detailed medical
investigation records were
considered for further genomic
analysis. Samples were
classified based on the
provisional diagnosis or based
on the symptoms into major
cohorts such as Cardiology,
Neurology, Primary
Immunodeficiency, Cleft Lip &
Cleft Palate, Sudden cardiac
death, Lysosomal storage
disorders, Haematology and
Dermatology. After DNA isolation and quality checks, the NGS libraries were prepared. The
samples were subjected to whole exome sequencing and analysis. In parallel, for each cohort

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