Universal multi-gene panel testing for individuals with pheochromocytomas and paragangliomas

Abstract Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) (PPGLs) are a genetically heterogeneous entity, with roughly 25-40% of cases found to harbor a pathogenic or likely pathogenic germline alteration. Existing practice guidelines advocating for the use of a sequential gene testing strategy to identify individuals with hereditary PPGL are driven by the presence of specific clinical features and predate the routine use of multigene panel testing (MGPT). Here we describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort from a diagnostic laboratory. Methods: Demographic and clinical information of individuals undergoing targeted MGPT for hereditary PPGL were collected from test requisition forms and supporting clinical documents provided by the ordering clinician and retrospectively reviewed. Individuals underwent MGPT of 10-12 genes depending on test order date. From August 2013 through May 2015, 560 individuals had targeted MGPT that included 10 genes (NF1, MAX, SDHA/B/C/D/AF2, RET, TMEM127, and VHL), and from May 2015 through December 2019, 1167 individuals had panel testing of 12 genes due to the addition of MEN1 and FH. Results: Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Out of all PVs, most were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.8%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, diagnosis before the age of 45 years, multiple tumors, and positive family history (fhx) of PPGL. Affected individuals with a fhx of PPGL were the most likely to have a PV (70.6% of individuals with PCC + fhx; 85.9% of individuals with PGL + fhx). The positive rate in nearly all clinical subgroups even without predictors of a PV remained over 10%, including individuals with a single tumor (PCC = 16.7%; PGL = 46.7%) and those without a fhx (PCC and negative fhx = 15.8%; PGL and negative fhx = 43.7%). Restricting genetic testing of hereditary PPGL to only SDHB/C/D genes misses a third (31.8%) of individuals with PVs. Among individuals with PVs in syndromic genes, over half (41.5%) did not have any additional syndromic features beyond PPGL reported by the ordering clinician. Conclusion: Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, numerous individuals with syndromic PVs presenting with isolated PPGL, and a substantial contribution to diagnostic yield from rare genes when included in testing. These findings support updating practice guidelines to incorporate universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.