Mapping a gene for Noonan syndrome to the long arm of chromosome 12

Noonan syndrome is characterized by typical facies, short stature and congenital cardiac defects. Approximately half of all cases are sporadic, but autosomal dominant inheritance with variable expression is well established. We have performed a genome-wide linkage analysis in a large Dutch kindred with autosomal dominant Noonan syndrome, and localized the Noonan syndrome gene to chromosome 12 (Zmax = 4.04 at 0 = 0.0). Linkage analysis using chromosome 12 markers in 20 smaller, two-generation families gave Zmax = 2.89 at 0 = 0.07, but haplotype analysis showed non-linkage in one family. These data imply that a gene for Noonan syndrome is located on chromosome 12q, between D12S84 and D12S366.