Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams–Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25–27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln^+/−; Rag1^−/− mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln^+/− mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.

中文翻译：

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Williams-Beuren 综合征患者的全外显子组测序以及小鼠的疾病建模指出了四种可能改变狭窄风险的新途径。

瓣上主动脉狭窄 (SVAS) 是由弹性蛋白 ( ELN ) 单倍体不足引起的主动脉狭窄。威廉姆斯-博伦综合征 (WBS) 患者的 SVAS 严重程度各不相同，这是一种罕见的疾病，会去除一个ELN副本和 25-27 个其他基因。20% 的 WBS 儿童需要一种或多种侵入性且通常具有风险的手术来纠正缺陷，而 30% 的儿童虽然具有相同的基本遗传病变，但没有明显的狭窄。没有已知的药物疗法。因此，鉴定修饰 SVAS 的基因为新的基于修饰剂的疗法提供了潜力。为了提高我们罕见疾病队列的统计功效 ( N = 104 个外显子组），我们利用了极端表型队列、功能性变异过滤和基于通路的分析。外显子组关联数据的基因集富集分析发现，与 SVAS 严重程度相关的基因中适应性免疫系统变异负担增加。额外的富集，仅使用已知在极端表型子集之间频率不同的潜在致病变异，确定了 SVAS 严重程度不仅与免疫通路基因，而且与细胞外基质、G 蛋白偶联受体信号传导和脂质代谢相关的基因的显着关联使用 SKAT-O 和 RQTest。Eln ^{+/- 的}补充学习；Rag1 ^-/-缺乏功能性适应性免疫系统的小鼠显示 ELN 不足的心血管特征有所改善。同样，对混合背景Eln ^+/-小鼠的研究证实，增加弹性纤维沉积的基因变异也对主动脉口径产生积极影响。通过使用工具来提高统计功效并结合小鼠的正交分析，我们检测到导致 SVAS 风险的四种主要途径。