Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome
ABSTRACT Noonan syndrome is an autosomal dominant disorder with an estimated incidence of 1 in 1,000 to 1 in 2,500 live births. It is characterized by postnatal-onset short stature, characteristic facial changes, webbed neck, pectus carinatum, or excavatum, congenital heart defects, and bleeding abnormalities. Gain-of-function mutations in the PTPN11, KRAS, SOS1, and RAF1 genes that are components of the RAS/MEPK signaling pathway are identified in about 70-85% of individuals with Noonan syndrome. We report here a case of duplication of chromosome region 12q24.11q24.23 identified by array comparative genomic hybridization (aCGH) that includes the PTPN11 gene in a 3-year-old girl with apparent Noonan syndrome. The patient presented with postnatal-onset failure-to-thrive, developmental delay, microcephaly, velopalatal incompetence, pectus excavatum, coarctation of aorta, atrial and ventricular septal defects, decreased muscle tone, and minor facial anomalies consistent with Noonan syndrome. At 3 years of age her speech, gross and fine motor development were at the level of a 12-18 month old child. This degree of developmental delay was atypical for an individual with Noonan syndrome, raising concerns for a chromosomal abnormality. Array-CGH showed an interstitial duplication of 10 Mb including the PTPN11 gene. Sequencing of PTPN11, KRAS, SOS1 and the coding region of RAF1 did not identify mutations. The increased gene dosage of the PTPN11 gene in the form of duplication is expected to have the same consequence as gain-of-function mutations seen in Noonan syndrome. We propose that at least some of the 15-30% of individuals with Noonan syndrome who do not have a mutation by sequencing may have a gain in copy number of PTPN11 and recommend that comprehensive testing for Noonan syndrome should include analysis for copy number changes of PTPN11.
- SourceAvailable from: Ann-Charlotte Thuresson[Show abstract] [Hide abstract]
ABSTRACT: The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about 1/4 of patients. To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assay was developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.European journal of medical genetics 03/2010; 53(3):117-21. DOI:10.1016/j.ejmg.2010.03.001 · 1.49 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.Molecular syndromology 02/2010; 1(1):2-26. DOI:10.1159/000276766
- American Journal of Medical Genetics Part A 08/2009; 149A(8):1846-9. DOI:10.1002/ajmg.a.32981 · 2.05 Impact Factor