Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited.
Our objectives were to estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance.
Nationwide retrospective cohort study.
Tertiary referral centers in the Netherlands (multicenter).
Germline SDHA analysis was performed in 393 genetically unexplained PGL-patients. Subsequently 30 index SDHA mutation carriers and 56 non-index carriers were studied.
The main outcome measures were SDHA mutation detection yield, clinical manifestations and SDHA-related disease penetrance.
Pathogenic germline SDHA variants were identified in 30 of the 393 referred PGL patients (7.6%), with either head and neck PGL (21/174=12%), pheochromocytoma (4/191=2%) or sympathetic PGL (5/28=18%). The median age at diagnosis in index SDHA mutation carriers was 43 years (range, 17 to 81) compared to 52 years (range, 7-90) in non-mutation carriers (p=0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 (95% CI 0-21%) in non-index mutation carriers.
Germline SDHA mutations are relatively common (7.6%) in genetically unexplained PGL patients. The majority of index patients presented with apparently sporadic PGL. In the largest SDHA series assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed.
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