DISCUSSION
In this study, we cataloged and estimated the mutational burden of known
pathogenic or clinically relevant variants in different Indian
populations. Our study showcases its applicability by evaluating the
mutational load in rare and complex disorders in Indian populations. As
an elaborated example, we have analysed frequency spectrum of mutations
in cystic fibrosis and different classes of Inborn errors of metabolism
in Indian context. In addition, our study provides, a comprehensive
knowledge of underrepresented prevalent and common genetic variants in
hereditary cancer associated genes, monogenic diabetes and Neuro and
Neuromuscular disorders.
This study suggests that pathogenic variants with high carrier frequency
are important candidates for prioritization in genetic testing. On the
other hand, absence of frequency for ~88% of known
pathogenic variants in Indian populations demonstrate the need of
cataloging and including population specific rare pathogenic variants in
public databases as well as in commercial assays or genotype chips.
Importantly, this study is an a priori guide for conducting genetic
screening studies which will benefit clinicians and researchers for
decision making as well as may aid in reducing genetic screening costs
using informative / uninformative estimates from our catalog.
This study also highlighted the fact that reliable estimates of carrier
frequency are required to estimate the real mutation load which cannot
be accurately estimated from literature based cataloging as well as only
patient data.
In addition to pathogenic variants, we also evaluated the effect of
those variants whose clinical significance is uncertain in ClinVar. We
used consensus of three predictive tools to ascertain their effect. Out
of 5,984 such variants, there are 3,751 variants that are predicted to
be detrimental. These variants are not part of the main analysis but a
list is provided in the database for the users. In addition, we also
cataloged variants that are important from pharmacogenetics perspective