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