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

Aim Multiple 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, namely RET, MEN1 and CDKN1B respectively. 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 Methods Using the gold-standard ACMG/AMP guidelines for variant classification, we have systematically classified variants reported across the RET, MEN1 and CDKN1B genes 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. Results We 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 pathogenic RET mutations 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: We have also designed an NGS primer panel across two pools covering all 33 exonic regions of the three genes through 38 amplicons. Conclusion Our 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the CNP-0007 project funded by the Council for Scientific and Industrial Research (CSIR-India) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: