Genetic Testing for Paraganglioma Patients

Primary Recommendations

The American College of Medical Genetics recommends that all patients diagnosed with paraganglioma should be offered genetic testing regardless of age at presentation, family history, or whether the tumor appears sporadic, as approximately 30-35% of all paragangliomas are hereditary 1, 2, 3
Genetic testing is justified because even apparently sporadic cases harbor germline mutations in 5.6-14% of patients, highlighting the importance of universal testing 1, 2, 4

The National Comprehensive Cancer Network recommends DNA sequencing and deletion/duplication testing for the following genes: SDHB, SDHD, VHL, RET, NF1, FH, and MEN1, as these are associated with paraganglioma 1, 2, 3, 5
SDHB is critical due to its high malignancy risk (30-40% metastatic potential) and aggressive behavior 1, 6
SDHD accounts for 6.2% of all paragangliomas 3, 5
VHL is associated with von Hippel-Lindau syndrome 3, 5
RET is associated with MEN2 syndrome 3, 5
NF1 should be included if neurofibromatosis has not been ruled out clinically 1, 2
FH should be included if hereditary leiomyomatosis syndrome has not been excluded clinically 1, 2
MEN1 may be included, though paragangliomas are rare in this syndrome 1, 2

The European Society of Medical Genetics recommends DNA sequencing (with deletion testing when appropriate) for SDHA, SDHC, SDHAF2, TMEM127, and MAX, as these genes are associated with paraganglioma, although the evidence for their inclusion is limited 1, 3, 5, 7
SDHA is most commonly associated with gastric GISTs in SDH-related tumors 7
SDHC accounts for 2% of all paragangliomas 1
SDHAF2 is rare but important for surveillance planning 3, 5
TMEM127 is found in 0.6-2% of cases 1
MAX is found in 1.1% of cases 1

The American College of Medical Genetics recommends that large deletion/duplication analysis is essential and must be included, as standard sequencing alone will miss these mutations 1, 2
Large deletions represent 11-19% of all pathogenic variants in SDHB, SDHC, and SDHD 1, 2
Up to 30% of VHL mutations are large deletions 1, 2

The National Comprehensive Cancer Network recommends that DNA from peripheral blood is the preferred specimen for germline testing, as tumor tissue analysis is not performed in routine clinical practice 1, 2
Tumor tissue analysis should only be used to confirm a variant detected in peripheral blood is germline rather than somatic 1, 2

The American Society of Clinical Oncology recommends that deletion/duplication testing should not be skipped, as this will miss 11-30% of pathogenic variants depending on the gene 1, 2
Family history should not be relied upon, as even "sporadic" cases have germline mutations in 5.6-14% of cases 1, 2
Phenotype-based algorithms should not be used, as they are outdated and miss hereditary cases 1, 2
Tumor tissue alone should not be tested, as germline testing from blood is required to distinguish hereditary from somatic mutations 1, 2