Genomic duplication of PTPN11is an uncommon cause of Noonan syndromeHow to cite this article: Graham JM Jr, Kramer N, Bejjani BA, Thiel CT, Carta C, Neri G, Tartaglia M, Zenker M. 2009. Genomic duplication of PTPN11is an uncommon cause of Noonan syndrome. Am J Med Genet Part A 149A:2122–2128.

Noonan syndrome NS is a genetically heterogeneous disorder caused most commonly by activating mutations in PTPN11. We report a patient with hypotonia, developmental delay and clinical features suggestive of NS. Highresolution chromosome analysis was normal, and sequence analyses of PTPN11, SOS1, KRAS, BRAF, RAF1, MEK, and MEK2were also normal. Array CGH revealed a single copy gain of 9 BAC clones at 12q24.11q24.21 8.98 Mb in size, which encompassed the PTPN11locus at 12q24.13 and was confirmed by FISH analysis. Shchelochkov et al. Shchelochkov et al. 2008; Am J Med Genet Part A 146A:1042–1048 reported a similar case and speculated that such duplications might account for 15–30 of NS cases with no detectable mutation in NS genes. We screened more than 250 NS cases without mutation in known NS diseasecausing genes by quantitative PCR, and none of these studies produced results in the duplicated range. We also explored the possibility that de novo changes affecting the untranslated region UTR of the PTPN11transcript might represent an alternative event involved in SHP2 enhanced expression. DHPLC analysis and direct sequencing of the entire 3′ UTR in 36 NS patients without mutation in known genes did not show any diseaseassociated variant. These findings indicate that duplications of PTPN11represent an uncommon cause of NS, and functionally relevant variations within the 3′UTR of the gene do not appear to play a major role in NS. However, recurrent observations of NS in individuals with duplications involving the PTPN11locus suggest that increased dosage of SHP2 may have dysregulating effects on intracellular signaling. © 2009 WileyLiss, Inc.