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than 20 years at IGIB. Megalencephalic leukoencephalopathy is a debilitating neurological
disease that is currently managed through anti-epilepsy medication but is essentially incurable.
Sridhar Sivasubbu and Vinod Scaria undertook work to understand the mutation spectrum in a
large Nalbund community comprising over 5000 individuals in Agra and Jaipur suffering from this
disease. Using exome sequencing a putative founder mutation was identified in the MLC1 gene
mutations, which are known to cause Megalencephalic leukoencephalopathy. A low-cost
diagnostic test was developed for this mutation. Community level screening became feasible at
an affordable price of about Rs. 2000 per test. Almost 30% of the community members were
carriers for this mutation and about 10% of the screened individuals have a homozygous
mutation that causes the disease. Such tests are valuable for enabling genetic counselling and
may pave the way for correction by gene editing in future.

Another focus area is cardiology, where samples of patients and family members suffering from
arrhythmia and cardiac hypertrophy were collected and subjected to whole exome sequencing.
Epidermolysis bullosa is a rare, but currently incurable genetic condition marked by skin that
readily blisters, the associated disfigurement can take a heavy toll on patients. It is a part of
Genodermatosis, a group of genetically inherited skin diseases. A total of 44 samples were
subjected to whole exome sequencing. The causative variation was successfully identified in 78%
of the patient samples. Of these 73% of mutations were present in a single gene. This single gene
is therefore a template for developing affordable diagnostic assays in commercial settings.

DECIPHERING IDIOPATHIC INTELLECTUAL DISABILITY (DIID) THROUGH NEXT
GENERATION SEQUENCING

Intellectual Disability (ID) is clinically as well as etiologically heterogeneous disorder that affects
up to 2-3% of the population. Routinely, patients with intellectual disability are screened using
either karyotyping for known chromosomal syndromes such as Down’s syndrome, chromosomal
microarray (CMA) to identify submicroscopic aberrations on a genome wide level or targeted
molecular testing for a suspected ID causing single gene disorder. Next-generation sequencing
is the latest emerging technique that allows detection of single-nucleotide changes either
throughout the whole genome or whole exome. (WGS/WES). Hence, it offers the possibility to
identify the genetic cause for patients, in which all previously available genetic tests, including
karyotyping, specific gene analysis, or microarray analysis do not reveal any causative
abnormalities.

The DIID-NGS project was initiated by Vinod Scaria at IGIB in April 2018 in collaboration with
AIIMS, Delhi. In this phase, the patients suffering from idiopathic intellectual disability were
systematically evaluated by a clinical geneticist at AIIMS and blood samples of those patients
along with unaffected family members were sent to IGIB. For a detailed evaluation, a clinical
proforma was formulated.

In this project, a stepwise approach is being followed in a phased manner to evaluate the
diagnostic yield of WES in patients with idiopathic intellectual disability. The patients are being
selected based upon the inclusion criteria and would undergo a thorough evaluation and filling
of proforma by a geneticist. CMA will be done for all recruited cases and only negative cases are
being considered for WES to identify known and new causative genes. This will lead to the

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