Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Medicine II, University of Freiburg Faculty of Medicine, Freiburg, Germany.
J Med Genet. 2020 Feb;57(2):96-103. doi: 10.1136/jmedgenet-2019-106214. Epub 2019 Sep 6.
Pathogenic germline variants in subunits of succinate dehydrogenase (, and ) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.
Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the , or genes.
Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence truncating, missense, truncating and missense, with the opposite pattern apparent for HNPGL (p<0.001).
truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to . We propose that surveillance and counselling of carriers of should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
琥珀酸脱氢酶（、和）亚单位的致病变异体广泛与嗜铬细胞瘤-副神经节瘤（PPGL）综合征的疾病亚型相关。我们的目的是研究变异类型（即错义与截断）在确定肿瘤表型中的作用。
分析了包含 950 例 PPGL 和头颈部副神经节瘤（HNPGL）患者的三个独立数据集，以研究变异类型与肿瘤类型和与年龄相关的肿瘤风险的相关性。所有患者均为、或基因的致病性种系变异携带者。
与错义变异相比，截断 SDH 变异在临床病例中明显过表达，携带 截断变异的患者发生 PPGL 的风险显著更高（p<0.001），诊断年龄更早（p<0.0001），与携带错义变异的患者相比，PPGL/HNPGL 合并症的风险更高。携带 截断变异的患者发生 PPGL 的风险呈增加趋势，而所有三个 SDH 基因在 HNPGL 病例中均表现出错义变异过度表达的趋势。总体而言，变异类型在 PPGL 中赋予风险的顺序为（从高到低）截断>错义>截断>错义，而在 HNPGL 中则呈现相反的模式（p<0.001）。
截断变异代表一个独特的群体，其临床表型与但不完全与相似。我们建议根据变异类型定制对携带者的监测和咨询。截断 SDHx 变异的临床影响与错义变异不同，表明残余 SDH 蛋白亚单位功能决定疾病的风险和部位。
