Abstract：
OBJECTIVE: Multiple Endocrine Neoplasia (MEN) is a group of familial cancer syndromes that encompasses several types of endocrine tumors differentiated by genetic mutations in RET, MEN1 and CDKN1B genes. Accurate diagnosis of MEN subtypes can thus be performed through genetic testing. However, MEN variants remain largely understudied in Indian populations. Additionally, few dedicated resources to understand these disorders currently exist.
METHODS: Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification.
RESULTS: We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb.
CONCLUSIONS: Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.
METHODS: Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification.
RESULTS: We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb.
CONCLUSIONS: Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.
摘要：
目的：多发性内分泌肿瘤（MEN）是一组家族性癌症综合征，包括通过RET基因突变而分化的几种类型的内分泌肿瘤，MEN1和CDKN1B基因。因此，可以通过基因测试对MEN亚型进行准确的诊断。然而,在印度人口中，男性变体仍未得到充分研究。此外,目前很少有专门的资源来了解这些疾病。
方法：使用黄金标准ACMG/AMP指南，我们系统地分类了IndiGen数据集中三个基因中报告的变异，并建立了印度人口中男性的遗传流行病学。我们进一步对ClinVar和Mastermind变体进行分类，并将所有变体编译到数据库中。最后,我们设计了一个用于快速变异鉴定的多重引物组。
结果：我们已经确定了MEN的遗传患病率如下：1026人中有1人可能患有与致病性RET突变相关的MEN。我们进一步创建了MAPVar数据库，其中包含3280个ACMG分类的变体，可在以下网址免费访问：https://clingen。igib.res.在/MAPVar/。最后,我们的NGS引物组通过38个扩增子覆盖了两个池的33个外显子区域，总扩增区域为65kb。
结论：我们的工作证明男性在印度是一种普遍的疾病。印度变体的罕见性质强调了基因组和功能研究以建立更全面的变体景观的必要性。此外,我们的小组提供了一种具有成本效益的基因检测方法，和MAPVar数据库是一个现成的参考，以帮助更好地了解临床和研究环境中的变异致病性。
方法：使用黄金标准ACMG/AMP指南，我们系统地分类了IndiGen数据集中三个基因中报告的变异，并建立了印度人口中男性的遗传流行病学。我们进一步对ClinVar和Mastermind变体进行分类，并将所有变体编译到数据库中。最后,我们设计了一个用于快速变异鉴定的多重引物组。
结果：我们已经确定了MEN的遗传患病率如下：1026人中有1人可能患有与致病性RET突变相关的MEN。我们进一步创建了MAPVar数据库，其中包含3280个ACMG分类的变体，可在以下网址免费访问：https://clingen。igib.res.在/MAPVar/。最后,我们的NGS引物组通过38个扩增子覆盖了两个池的33个外显子区域，总扩增区域为65kb。
结论：我们的工作证明男性在印度是一种普遍的疾病。印度变体的罕见性质强调了基因组和功能研究以建立更全面的变体景观的必要性。此外,我们的小组提供了一种具有成本效益的基因检测方法，和MAPVar数据库是一个现成的参考，以帮助更好地了解临床和研究环境中的变异致病性。
