8639 Clinical characterization and germline DNA methylation analysis of a large cohort of patients with paraganglioma syndrome type 4

Abstract Disclosure: R. Halperin: None. R. Horowitz: None. A. Jabarin: None. A. Tirosh: None. Background: Patients harboring germline pathogenic variant (PV) in the SDHB gene (Paraganglioma syndrome type 4, PPGL4) have a higher risk of developing paragangliomas and pheochromocytomas. PPGL4 is considered a higher-risk syndrome for aggressive and metastatic abdominal-thoracic paragangliomas compared with other paraganglioma syndromes. The penetrance in PPGL4 reaches 65% by the age of 80 years. Aims: To assess possible germline DNA epigenetic alterations in patients harboring the SDHB PV. Materials and Methods: A large cohort of patients with PPGL4 was characterized clinically in our clinic and genetically via germline DNA sequencing for the familial variant (SDHB c.640C>T p.Q214Ter, n=144) and whole genome methylation analysis compared 19 patients vs. 129 healthy controls. The control group consisted of four SDHB PV-negative family members and an additional 125 samples retrieved from a public database (GSE153712). Analysis was performed on Rstudio, using the ChAMP suite for normalization, imputation, differentially methylated probes (DMP), and regions (DMR) analyses. Pathway analysis and visualization were executed using the clusterprofiler and enrichplot packages. Promoter regions were defined by the transcription start site (TSS1500). Results: The cohort includes three kindreds, and each presented independently with an index patient: Index patient in kindred A, a 12-year-old boy, with thoracic paraspinal and testicular paragangliomas, non-secretory, requiring several surgeries due to spinal compression with subsequent improvement of neurological deficit. Index patient in kindred B, a 26-year-old woman with abdominal paraganglioma, metastatic to the lungs and spine. Index patient in kindred C, a 41-year-old man with a locally aggressive abdominal paraganglioma, metastatic to the skull and spine. A total of 114 (44.2% females) patients underwent genetic evaluation (45/50, 16/28, and 25/36 in kindreds A, B and C, respectively). Of those, 50 (58.1%) harbored the familial SDHB PV (68.9%, 56.2%, and 40.0%, respectively). Twenty-six patients underwent at least partial clinical evaluation: Eight had paraganglioma (4/8 had metastatic disease), three had pheochromocytoma, and two patients had neck masses that are currently being evaluated. Pathway analysis revealed enrichment of the germline DNA alterations to the regulation of cell differentiation and development, metabolic processes, and cellular component organization (p<0.03 for all pathways). Conclusions: We report one of the largest cohorts of patients with SDHB PV, showing typical low penetrance and aggressive phenotype. Genomic analysis shows distinct germline DNA methylation in SDHB PV-positive compared with the control group. Future studies may reveal an association between specific epigenetic alterations and penetrance/phenotypic patterns in this rare hereditary syndrome. Presentation: 6/2/2024