Research finds mutation that causes Noonan syndrome

Scientists have discovered that mutations in a gene known as SOS1 account for many cases of Noonan syndrome (NS), a common childhood genetic disorder that occurs in one in 1,000 to 2,500 live births. NS is characterized by short stature, facial abnormalities, and learning disabilities, as well as heart problems and predisposition to leukemia.

Led by researchers at Harvard Medical School-Partners Healthcare Center for Genetics and Genomics (HPCGG) and Beth Israel Deaconess Medical Center (BIDMC), the findings are reported in the December issue of Nature Genetics, which appeared online Dec. 4.

“Noonan syndrome is the most common single-gene cause of congenital heart disease,” explains co-senior author Benjamin Neel, director of the Division of Cancer Biology at BIDMC and a professor of medicine at Harvard Medical School (HMS).

“Although previous work had identified mutations in the PTPN11 gene as the cause of Noonan syndrome in nearly 50 percent of cases [and mutations in an oncogene known as KRAS in a small subset of severe cases], the identity of the gene or genes responsible for fully half the cases had not been elucidated,” Neel said.

To identify candidate genes, a group led by HMS instructor Amy Roberts and HPCGG’s scientific director Raju Kucherlapati conducted genetic analysis of more than 100 children with Noonan syndrome. This large cohort of NS patients had neither PTPN11 nor KRAS mutations.

This work was supported, in part, by grants from the National Institutes of Health and the National Center for Research Resources.