Page 49 - CSIR-IGIB Annual Report 2020-21

Translational research in Wilson's Disease ATP7A clinical genetics resource
Wilson’s Disease (WD) is one of the prevalent ATP7A is a critical copper transporter involved
genetic diseases globally. The Indian in Menkes Disease, Occipital horn Syndrome
Collaborative Research Network on Wilson’s and X-linked distal spinal muscular atrophy type
Disease (iCROWD) was created as a focused 3 which are X linked genetic disorders. These are
programme to understand the genetic and rare diseases and the genetic epidemiology of
clinical correlates of WD, a major pediatric these diseases is unknown. A number of genetic
chronic liver disease in the Indian subcontinent. variants in the genes have been reported in
iCROWD has three major components published literature as well as databases,
encompassing the clinical areas of WD, however, understanding the pathogenicity of
molecular genetic basis of WD, and disease variants and genetic epidemiology requires the
modelling. For each of the three areas we data to be compiled in a unified format. To this
propose to have a consortium approach to end, we systematically compiled genetic
deliver better diagnosis and personalized, variants from published literature and datasets.
precision medicine in WD clinical settings in Each of the variants were systematically
India. A pilot network of over 45 clinicians from evaluated for evidence with respect to their
over 20 centers across the country have already pathogenicity and classified as per the American
been established. We propose a common College of Medical Genetics and the Association
framework for exchange of datasets, resources of Molecular Pathologists (ACMG-AMP)
within the consortium and participatory guidelines into Pathogenic, Likely Pathogenic,
approach to realize the full potential of clinical Benign, Likely Benign and Variants of Uncertain
genomics. The activities would encompass a Significance. Additional integrative analysis of
standardized approach to sequence data population genomic datasets provides insights
generation, computational analysis of genomic into the genetic epidemiology of the disease
data, integration, sharing and communication. through estimation of carrier frequencies in
Through this approach, diagnosis is provided for global populations. To deliver a mechanistic
cases, which present with a known and explanation for the pathogenicity of selected
classified variant. For novel variants and genes variants, we also performed molecular
identified, in-depth assays would be established modeling studies. Our modeling studies
including in vitro approaches. This would permit concluded that the small structural distortions
obtaining patient-specific biological data and observed in the local structures of the protein
finally one could use that to customize patient may lead to the destabilization of the global
specific clinical solution. The validated novel structure. To the best of our knowledge, our
variants in the population and specific assays for ATP7A Clinical Genetics Resource is one of the
the WD disease are available for community most comprehensive compendia of variants in
screening, prenatal testing and forms the core the gene providing clinically relevant
for intellectual property which could be annotations in gene.
exploited for societal/commercial applications.
We also propose to create a unique resource Novel lead molecule development -CDK5
that would systematically curate, store, analyse inhibitor
and disseminate information contributed by The pharmaceutical industry has clearly come to
individual investigators. Such a hub would serve fully recognize the protein kinase family as a rich
as a ready reference for interpreting genetic source of therapeutic targets. The growing
variations, especially novel variants in WD, arsenal of protein kinase inhibitors will clearly
significantly reducing the cost of validation. This have a profound impact on the treatment of
would serve as a ready reference for clinicians human diseases. We have screened 25,000
and clinical geneticists. compounds from the kinase inhibitor library,
and 19 inhibitors were selected. The 19

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