背景：主动脉瓣上狭窄（SVAS）是Williams-Beuren综合征（WBS）的特征性特征。其严重程度各不相同：约20％的Williams-Beuren综合征患者患有需要手术干预的SVAS，而约35%没有明显的SVAS。其余个体具有中等严重程度的SVAS。对导致这种变异性的遗传修饰剂知之甚少。
结果：我们对473名Williams-Beuren综合征患者进行了基因组测序，并开发了在这种罕见疾病人群中发现修饰剂的策略。方法包括极端表型和非同义变体优先排序，然后进行基因集富集和通路水平关联试验。我们接下来使用GTExv8和蛋白质组数据集来验证相关组织中候选修饰剂的表达。最后,我们评估了此处确定的基因/途径与通过较大的主动脉疾病/性状全基因组关联研究确定的基因/途径之间的重叠.我们表明，Williams-Beuren综合征的SVAS严重程度与母系和免疫途径中常见和稀有变异的频率增加有关。两个相关的母系基因(ACAN和LTBP4)在主动脉中独特地表达。先前已在动脉瘤的全基因组关联研究中报道了已识别通路中的许多基因，二叶主动脉瓣,或主动脉大小。
结论：在罕见疾病研究中较小的样本量需要新的方法来检测修饰因子。我们的策略确定了与SVAS严重程度相关的母系和免疫途径的变化。这些发现表明,像其他主动脉病变一样,SVAS可能受基质蛋白质合成和降解平衡的影响。利用以主动脉为中心的大型全基因组关联研究的多项数据和结果，可能会加速SVAS等罕见主动脉病变的修饰发现。
BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability.
RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size.
CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
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