Assessment of the penetrance of mutations/deletions in the SDHB and SDHD genes

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla (pheochromocytomas, 80%-85%) or extra-adrenal paraganglia (paragangliomas, 15%-20%), respectively. PPGLs have the highest heritability among endocrine tumors. Currently, about 40% of PPGL individuals have a genetic germline mutation and at least 12 different genetic syndromes are related to these tumors, such as multiple endocrine neoplasia types 2, von Hippel-Lindau disease, neurofibromatosis type 1, and SDHx paraganglioma syndromes. The PPGL susceptibility genes can be divided into two clusters: cluster 1 includes the von Hippel-Lindau suppressor gene (VHL) and the four subunits of the succinate dehydrogenase complex (SDHA, SDHB, SDHC, and SDHD), among others. Cluster 2 includes the neurofibromatosis type 1 gene (NF1), the rearranged during transfection proto-oncogene RET), genes encoding transmembrane protein 127 (TMEM127), and MYC-associated factor X (MAX). Paraganglioma, multifocal or metastatic disease, familial history, or the age of diagnosis <45 years are associated with a higher risk of having germline mutation. Cluster 1 gene mutations are more prevalent in children with PPGLs. Penetrance of SDHB and SDHD mutations varies from 15% to 50% in PPGL cohorts, but it has not been evaluated in Brazilian kindreds with mutations in these genes. Therefore, our aim is to investigate the penetrance of SDHB and SDHD mutations (particularly SDHB exon 1 deletion) in Brazilian kindreds with PPGLs.(AU)