Understanding the variant landscape, and genetic epidemiology of Multiple Endocrine Neoplasia in India

Abstract

AbstractAimMultiple Endocrine Neoplasia (MEN) is a familial cancer syndrome that encompasses several different types of endocrine tumors. The disease has three main types, namely MEN1, MEN2 and MEN4 that may or may not overlap phenotypically, but are caused by genetic mutations in three different genes, namelyRET, MEN1andCDKN1Brespectively. Genetic testing for effective diagnosis, improved prognosis, and treatment is recommended as part of of clinical practice guidelines, which makes establishment of accurate pathogenicity classification of variants across the three genes essential. However, few resources offer such classification, especially in a population specific manner.Materials and MethodsUsing the gold-standard ACMG/AMP guidelines for variant classification, we have systematically classified variants reported across theRET, MEN1andCDKN1Bgenes reported in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We have additionally classified variants from ClinVar and Mastermind, and made all variant classifications freely accessible in the form of a database called MAPVar. Finally, we have designed a primer panel for accurate, cost-effective diagnosis of the three MEN types.ResultsWe have established the genetic prevalence of MEN in the Indian population to be the following: 1 in nearly 341 individuals is a likely carrier of MEN linked pathogenicRETmutations in the Indian population.We have compiled ACMG-classified variants from three large datasets to create an exhaustive compendium of MEN-linked variants called MEN-Associated Pathogenic Variants (MAPVar). The database is available at:https://clingen.igib.res.in/MAPVar/We have also designed an NGS primer panel across two pools covering all 33 exonic regions of the three genes through 38 amplicons.ConclusionOur work establishes that MEN is prevalent disorder in India, with MEN2 variants being the most reported of the three types. This indicates the need of more genomic studies of MEN variants to establish a more comprehensive variant landscape specific to Indian populations.Additionally, genetic testing is an effective tool used against MEN. Our panel offers a means of swift testing, and the MAPVar resource offers an exhaustive compendium of ACMG-classified MEN variants, that can act as a ready reference to aid in interpretation of genetic testing results, as well as better understanding genetic variants in clinical as well as research settings.