<i>SDHB</i> variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

Abstract

Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link <i>SDHB</i> variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and <i>SDHD</i> variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for <i>SDHD</i> variants. In the present study we zoom in on the genotype-phenotype associations of <i>SDHB</i> gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating <i>SDHB</i> variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. Compared with missense variants, truncating <i>SDHB</i> variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. <i>SDHB</i> truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.