Purpose

The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data.

Methods

This study uses exome sequencing and corresponding phenotypic data from Mount Sinai’s BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1.

Results

Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5).

Conclusions

Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.

中文翻译：

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探索具有明显外部表现的孟德尔心血管特征的基因型优先方法

目的

本研究的目的是使用基因型优先的方法，利用生物库数据探索具有外部特征的高渗透性、常染色体显性遗传心血管疾病、RASopathies 和马凡综合征 (MFS)。

方法

本研究使用来自西奈山 Bio Me ( n  = 32,344) 和英国生物银行 (UKBB; n = 49,960) 的外显子组测序和相应的表型数据 。变异管理确定了 RASopathy 基因和FBN1中的致病/可能致病 (P/LP) 变异。

结果

21 名受试者携带 P/LP RASopathy 变异；3 人 (14%) 被诊断出，另外 46% 有≥1 个经典努南综合征 (NS) 特征。主要 NS 特征（身材矮小 [9.5% p  = 7e-5] 和心脏异常 [19%, p  < 1e-5]）的频率低于预期。与生物库人群相比，甲状腺功能减退/自身免疫性疾病的患病率更高（p  = 0.007）。对于具有FBN1 P/LP 变异的受试者，14/41 (34%) 具有 MFS 诊断或高度提示特征。有超声心动图数据的 15 名参与者中有 5 名 (33%) 有主动脉扩张，少于预期 ( p  = 8e-6)。晶状体异位仅影响 15% ( p  < 1e-5)。

结论

携带与 RASopathy 或 MFS 部分或全部表型匹配的 P/LP 变体的个体中有相当一部分仍未得到诊断，有些不符合诊断标准。常规人群基因分型将实现多学科护理并避免危及生命的事件。