The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

RASopathies 是一组由 RAS/MAPK 信号通路失调引起的临床和遗传异质性发育障碍。该途径的几种成分和调节剂的变异已被确定为致病原因。2015 年，在临床诊断为 Noonan 综合征 (NS) 的三个不相关家族中报告了A2ML1的错义变异，并且提出了一个斑马鱼模型，显示心脏和颅面缺陷类似于由 NS 相关的 Shp2 变异引起的缺陷。然而，此后 A2ML1变体在 NS 中的因果作用尚未得到证实。在此，我们报告了 15 名接受 RASopathy 相关基因筛查并被发现携带A2ML1罕见变异的个体，包括以前提出的导致 NS 的变体。在父母 DNA 可用的情况下，发现相应的A2ML1变体遗传自未受影响的父母。七名携带A2ML1变体的指数患者出现了另一种引起疾病的遗传异常。这些发现强调，目前的证据不足以支持A2ML1和 NS 变异之间的因果关系，质疑将A2ML1筛查纳入诊断性 RASopathy 测试。