Germline Multigene Panel Testing in Japanese Patients with Pheochromocytoma and Paraganglioma: Technical Feasibility and Clinical Utility.

Abstract

Background: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with a high rate of germline predisposition. Although multigene panel testing (MGPT) using next-generation sequencing (NGS) is widely adopted globally, its clinical application in Japan remains limited. Methods: We developed a custom amplicon-based NGS panel targeting 12 established PPGL susceptibility genes. Germline analysis was performed in 23 Japanese patients with confirmed PPGL to evaluate sequencing quality and variant detection. Results: Sequencing quality was consistently high (Q30 > 96%, mapping rate >99%, on-target rate >80%), with nearly all exons (148/149) achieving >1,000× coverage. Pathogenic or likely pathogenic variants were found in 21.7% (5/23), including SDHB, VHL, and RET. In addition, variants of uncertain significance (VUS) were found in 17.4% (4/23), including novel missense variants in FH, SDHA, and MAX. Conclusions: This study demonstrates the feasibility and clinical utility of amplicon-based MGPT for PPGL in a real-world Japanese setting and highlights the importance of ongoing VUS reclassification to improve clinical interpretation. The findings support its diagnostic value, reflect underlying clinical demand, and contributed to its non-insured clinical adoption at certified laboratories in Japan.