Evaluating Patterns of SDHx Tumor Presentation by Gene and Variant Type: A Retrospective Analysis of a Large Clinical Cohort

PURPOSEPheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. It is estimated 40% of PCCs/PGLs can be described by hereditary causes, most often in the SDHx genes (SDHx: SDHA/B/C/D), resulting in heterogeneous clinical tumor findings. Previous research suggests a possible genotype-phenotype association. This study aimed to explore associations between pathogenic variant (PV) type and tumor presence. METHODSA prospectively maintained database at an academic medical center was used to identify individuals with SDHx PVs. The research team abstracted demographics, clinical, genomic, and variant information from the electronic medical record for analysis. Additional variant data were collected through the University of California Santa Cruz Genome Browser and MutationTaster2021 outputs. Descriptive and comparative analyses were run using R*Stats (R Foundation for Statistical Computing, Vienna, Austria). RESULTSIn this study, 304 individuals with SDHx PVs had 111 tumors, across 89 kindreds. The cohort reflected well-established penetrance estimates and gene-specific tumor type risk. In addition, this analysis points toward additional factors that could be incorporated into risk assessment, including age, variant type, and variant location within gene. CONCLUSIONExploration of these associations further supports the need for gene-specific screening recommendations.