Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi‐commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare.

中文翻译：

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ADAMTS19相关的心脏瓣膜缺陷：巩固可识别心脏表型的新型遗传变异。

最近，ADAMTS19被确定为常染色体隐性心脏瓣膜病（HVD）的新型致病基因，主要影响主动脉瓣膜和肺动脉瓣膜。进行了外显子组测序和数据存储库（CentoMD）分析，以鉴定具有ADAMTS19变体（两个家族）的患者。基于心脏表型相似性和SNP阵列纯合性，认识到第三个家族。在来自三个家庭的六名患者中鉴定出三个新的功能丧失（LoF）变异体。临床上，所有患者均出现主动脉/肺动脉瓣异常，包括瓣膜小叶增厚，狭窄和功能不全。3例患者（主动脉）膜下（复发），提示ADAMTS19是第一个与离散主动脉瓣狭窄相关的基因。1例出现双合瓣肺动脉瓣。所有患者均表现出一定程度的房室瓣膜功能不全。其他心脏异常包括心房/心室间隔缺损，持续性动脉导管未闭和轻度扩张的升主动脉。我们的发现证实，ADAMTS19中的双等位基因LoF变异是导致特定和可识别的心脏表型的原因。我们建议对所有多发性半月形瓣膜异常的患者，尤其是存在主动脉膜下的患者，考虑进行ADAMTS19基因检测。ADAMTS19 需要对半月瓣异常患者进行筛查，以估计与HVD相关的表型的频率，这种情况可能并不罕见。