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. 2023 Jan;60(1):25-32. doi: 10.1136/jmedgenet-2020-107656. Epub 2021 Nov 8.
Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for variants. In the present study we zoom in on the genotype-phenotype associations of 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 variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis.
Compared with missense variants, truncating 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.
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.
琥珀酸脱氢酶复合物 II（SDH）基因的传统基因型-表型相关性将变体与胸腹部嗜铬细胞瘤-副神经节瘤（PPGL）联系起来，而变体与头颈部副神经节瘤（HNPGL）联系起来。然而，在最近的一项研究中，我们发现了变体的强烈和特异性基因型-表型关联。在本研究中，我们关注基因变体的基因型-表型关联，考虑个体基因变体对疾病风险和恶性肿瘤风险的影响。
我们分析了两个独立的大型数据集，包括总共 448 名患有 PPGL 和 HNPGL 的患者，并使用二项式检验和 Kaplan-Meier 分析研究了错义或截断变体与肿瘤发生率、发病年龄和恶性肿瘤风险的关联。
与错义变体相比，截断变体在 PPGL 患者中明显且一致更为常见，相差 20 个百分点。与错义变体携带者相比，恶性肿瘤在截断变体携带者中也更为常见。两种变体类型的 PPGL 发病年龄之间没有总体差异，但在某些情况下，某些个别变体可能存在差异。错义变体在 HNPGL 患者中略为过度表达，但差异无统计学意义。
与错义变体相比，截断变体传达了发生 PPGL 和恶性肿瘤的风险增加。这些结果进一步支持了截断变体与 PPGL 之间的早期强关联，并且还表明两种变体类型在其对复合物 II 功能的影响方面存在差异，PPGL/HNPGL 组织对复合物 II 功能变化的敏感性不同。
