Molecular characterization of a balanced rearrangement of chromosome 12 in two siblings with Noonan syndrome

The etiology of Noonan syndrome (NS) has been greatly elucidated with the discovery of the disease causative genes PTPN11, KRAS, SOS1, and RAF1, all involved in the RAS/MAPK -signaling cascade. Given that overall mutations are identified in about 70% of patients, identification of other NS associated genes remains a high priority to fully understand the etiopathogenesis of the condition. We report two affected siblings with an apparently balanced rearrangement of chromosome 12 ins(12)(q12p11.2p12.3) which segregates with the Noonan phenotype. The rearrangement was inherited from the phenotypically normal mother who had mosaicism for the derivative chromosome 12. There were no mutations of PTPN11, KRAS, SOS1, or RAF1 genes detected in the probands. Using fluorescence in situ hybridization analysis we identified the three breakpoints involved at 12p12.3, 12p11.2, and 12q12. By microarray analysis, there were no gains or losses near the breakpoints. Neither, the PTPN11 or KRAS region on chromosome 12 was involved in the rearrangement. We hypothesize that other NS candidate gene(s) may be located in the breakpoint regions of chromosome 12 causing the Noonan phenotype in both of these children.