Molecular screening of family members at-risk of developing pheochromocytoma due to germline mutation in the TMEM127 and SDHB genes

• Grant number: 23/11889-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2024
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Delmar Muniz Lourenço Jr
• Grantee: Isabella Gonçalves da Motta
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Molecular screening of at-risk relatives belonging to families with documented pheochromocytoma/paraganglioma (PPGL) with germline mutation is known to be essential for early diagnosis and treatment. There are, however, 111 index cases reported with mutation in the TMEM127 gene and only 15% of them had a positive family history. Tracing relatives at risk is, still, very little evaluated in these cases. As the evolutionary behavior can be very different in relatives compared to that observed in index cases, the systematic screening of relatives may help in understanding the clinical presentation and data previously published by us, estimating the penetrance of PPGL in 33% of mutation cases germline TMEM127. In parallel, a few families of Portuguese origin with a founder mutation in the SDHB gene have been described in both Portugal and Brazil. We recently identified an index case with malignant PPGL with this founding mutation, a deletion of exon 1 of the SDHB gene. We intend to expand the genealogy of this family and offer molecular screening to at-risk parents and describe the phenotype of this family by comparing it with the findings in the literature. We intend to provide, through molecular diagnostics, genetic counseling followed by early diagnosis and treatment of newly identified patients. In addition, we will systematically review the literature of PPGL associated with TMEM127 and reported cases with a founder mutation in the SDHB gene associated with the described clinical description of these very rare families.