Next-generation sequencing identifies rare variants associated with Noonan syndrome

Noonan syndrome (NS) is one of several RASopathies, which are developmental disorders caused by mutations in genes encoding RAS-ERK pathway components. The cause of 20–30% of NS cases remains unknown, and distinguishing NS from other RASopathies and related disorders can be difficult. We used next-generation sequencing (NGS) to identify causative or candidate genes for 13 of 27 NS patients lacking known NS-associated mutations. Other patients harbor single variants in potential RAS-ERK pathway genes, suggesting rare private variants or other genetic mechanisms of NS pathogenesis. We also found mutations in causative genes for other developmental syndromes, which together with clinical reevaluation, prompted revision of the diagnosis. NGS can aid in the challenging diagnosis of young patients with developmental syndromes.