Central nervous system developmental disorder in Noonan syndrome: a genomic approach

Noonan syndrome (NS – OMIM 163950) is a multisystemic dominant disorder with a prevalence of 1/1000-1/2500 live births. It is clinically and genetically heterogeneous, with mutations in several genes of the RAS/MAPK pathway detectable in up to 75% of cases. Pathogenesis of central nervous system (CNS) developmental anomalies has not been thus far fully enlightened. We have applied the multiple hit hypothesis to study in deep the pathogenic mechanisms implicated in NS related CNS anomalies. In this oligogenic model, point mutations and genomic rearrangements cooperate in an additive manner in the pathologic development of CNS. Using array CGH technology, we analyzed 15 samples of selected patients with molecularly confirmed diagnosis of NS and a severe impairment of CNS. We found 37 rare CNVs (one/several per patient) most of them inherited from an healthy parent. According to the Database of Genomic Variants 12/37 were never reported and 25/37 were reported in very few cases. Based on the function of the genes mapping in the identified CNVs, 10/37 (27%) were probably involved in the pathogenesis of CNS anomalies observed in our patients. We provided first data supporting the hypothesis that CNS involvement in NS does not depend exclusively on single gene mutations but also on the concurrent presence of other genomic penetrant variants. These results represent an initial assumption for the application of the multi-hit hypothesis in the dissection of the NS pathogenesis. Further studies on larger cohorts are deserved to better define the meaning and the clinical implications of these findings.