Publications (8)46.64 Total impact
-
Article: Prevalence of sequence variants in the RAS-mitogen activated protein kinase signaling pathway in pre-adolescent children with hypertrophic cardiomyopathy.
[show abstract] [hide abstract]
ABSTRACT: Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.Circulation Cardiovascular Genetics 05/2012; 5(3):317-26. · 6.11 Impact Factor -
Article: A Fabry-Perot fiber-optic ultrasonic hydrophone for the simultaneous measurement of temperature and acoustic pressure.
[show abstract] [hide abstract]
ABSTRACT: A dual sensing fiber-optic hydrophone that can make simultaneous measurements of acoustic pressure and temperature at the same location has been developed for characterizing ultrasound fields and ultrasound-induced heating. The transduction mechanism is based on the detection of acoustically- and thermally-induced thickness changes in a polymer film Fabry-Perot interferometer deposited at the tip of a single mode optical fiber. The sensor provides a peak noise-equivalent pressure of 15 kPa (at 5 MHz, over a 20 MHz measurement bandwidth), an acoustic bandwidth of 50 MHz, and an optically defined element size of 10 microm. As well as measuring acoustic pressure, temperature changes up to 70 degrees C can be measured, with a resolution of 0.34 degrees C. To evaluate the thermal measurement capability of the sensor, measurements were made at the focus of a high-intensity focused ultrasound (HIFU) field in a tissue mimicking phantom. These showed that the sensor is not susceptible to viscous heating, is able to withstand high intensity fields, and can simultaneously acquire acoustic waveforms while monitoring induced temperature rises. These attributes, along with flexibility, small physical size (OD approximately 150 microm), immunity to Electro-Magnetic Interference (EMI), and low sensor cost, suggest that this type of hydrophone may provide a practical alternative to piezoelectric based hydrophones.The Journal of the Acoustical Society of America 07/2009; 125(6):3611-22. · 1.55 Impact Factor -
Article: Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.
American Journal of Medical Genetics Part A 07/2007; 143A(11):1249-52. · 2.39 Impact Factor -
Article: Discriminating power of localized three-dimensional facial morphology.
[show abstract] [hide abstract]
ABSTRACT: Many genetic syndromes involve a facial gestalt that suggests a preliminary diagnosis to an experienced clinical geneticist even before a clinical examination and genotyping are undertaken. Previously, using visualization and pattern recognition, we showed that dense surface models (DSMs) of full face shape characterize facial dysmorphology in Noonan and in 22q11 deletion syndromes. In this much larger study of 696 individuals, we extend the use of DSMs of the full face to establish accurate discrimination between controls and individuals with Williams, Smith-Magenis, 22q11 deletion, or Noonan syndromes and between individuals with different syndromes in these groups. However, the full power of the DSM approach is demonstrated by the comparable discriminating abilities of localized facial features, such as periorbital, perinasal, and perioral patches, and the correlation of DSM-based predictions and molecular findings. This study demonstrates the potential of face shape models to assist clinical training through visualization, to support clinical diagnosis of affected individuals through pattern recognition, and to enable the objective comparison of individuals sharing other phenotypic or genotypic properties.The American Journal of Human Genetics 01/2006; 77(6):999-1010. · 10.60 Impact Factor -
Article: Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome.
[show abstract] [hide abstract]
ABSTRACT: Germline mutations in PTPN11--the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2--represent a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders, a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.The American Journal of Human Genetics 10/2004; 75(3):492-7. · 10.60 Impact Factor -
Article: 3D analysis of facial morphology.
[show abstract] [hide abstract]
ABSTRACT: Dense surface models can be used to analyze 3D facial morphology by establishing a correspondence of thousands of points across each 3D face image. The models provide dramatic visualizations of 3D face-shape variation with potential for training physicians to recognize the key components of particular syndromes. We demonstrate their use to visualize and recognize shape differences in a collection of 3D face images that includes 280 controls (2 weeks to 56 years of age), 90 individuals with Noonan syndrome (NS) (7 months to 56 years), and 60 individuals with velo-cardio-facial syndrome (VCFS; 3 to 17 years of age). Ten-fold cross-validation testing of discrimination between the three groups was carried out on unseen test examples using five pattern recognition algorithms (nearest mean, C5.0 decision trees, neural networks, logistic regression, and support vector machines). For discriminating between individuals with NS and controls, the best average sensitivity and specificity levels were 92 and 93% for children, 83 and 94% for adults, and 88 and 94% for the children and adults combined. For individuals with VCFS and controls, the best results were 83 and 92%. In a comparison of individuals with NS and individuals with VCFS, a correct identification rate of 95% was achieved for both syndromes. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.American Journal of Medical Genetics Part A 06/2004; 126A(4):339-48. · 2.39 Impact Factor -
Article: 3D analysis of facial morphology
[show abstract] [hide abstract]
ABSTRACT: Dense surface models can be used to analyze 3D facial morphology by establishing a correspondence of thousands of points across each 3D face image. The models provide dramatic visualizations of 3D face-shape variation with potential for training physicians to recognize the key components of particular syndromes. We demonstrate their use to visualize and recognize shape differences in a collection of 3D face images that includes 280 controls (2 weeks to 56 years of age), 90 individuals with Noonan syndrome (NS) (7 months to 56 years), and 60 individuals with velo-cardio-facial syndrome (VCFS; 3 to 17 years of age). Ten-fold cross-validation testing of discrimination between the three groups was carried out on unseen test examples using five pattern recognition algorithms (nearest mean, C5.0 decision trees, neural networks, logistic regression, and support vector machines). For discriminating between individuals with NS and controls, the best average sensitivity and specificity levels were 92 and 93% for children, 83 and 94% for adults, and 88 and 94% for the children and adults combined. For individuals with VCFS and controls, the best results were 83 and 92%. In a comparison of individuals with NS and individuals with VCFS, a correct identification rate of 95% was achieved for both syndromes. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html. © 2004 Wiley-Liss, Inc.American Journal of Medical Genetics Part A 04/2004; 126A(4):339 - 348. · 2.39 Impact Factor -
Article: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.
[show abstract] [hide abstract]
ABSTRACT: Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.The American Journal of Human Genetics 06/2002; 70(6):1555-63. · 10.60 Impact Factor
Top co-authors
Top Journals
Institutions
-
2004
-
St George Hospital
Sydney, New South Wales, Australia
-
