The clinical significance ofA2ML1variants in Noonan syndrome has to be reconsidered

摘要

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 inA2ML1were 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 ofA2ML1variants 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 inA2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respectiveA2ML1variant was found to be inherited from an unaffected parent. Seven index patients carrying anA2ML1variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants inA2ML1and NS, questioning the inclusion ofA2ML1screening in diagnostic RASopathy testing.