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Esposito G.,Kids Heart Research | Butler T.L.,Kids Heart Research | Butler T.L.,Heart Center for Children | Blue G.M.,Kids Heart Research | And 16 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

The majority of congenital heart disease (CHD) occurs as a sporadic finding, with a minority of cases associated with a known genetic abnormality. Combinations of genetic and environmental factors are implicated, with the recent and intriguing hypothesis that an apparently high rate of somatic mutations might explain some sporadic CHD. We used samples of right ventricular myocardium from patients undergoing surgical repair of tetralogy of Fallot (TOF) and hypoplastic left heart (HLH) to examine the incidence of somatic mutation in cardiac tissue. TOF is a common form of cyanotic CHD, occurring in 3.3 per 10,000 live births. HLH is a rare defect in which the left side of the heart is severely under-developed. Both are severe malformations whose genetic etiology is largely unknown. We carried out direct sequence analysis of the NKX2-5 and GATA4 genes from fresh frozen cardiac tissues and matched blood samples of nine TOF patients. Analysis of NKX2-5, GATA4, and HAND1 was performed from cardiac tissue of 24 HLH patients and three matched blood samples. No somatic or germline mutations were identified in the TOF or HLH patients. Although limited by sample size, our study suggests that somatic mutations in NKX2-5 and GATA4 are not a common cause of isolated TOF or HLH. © 2011 Wiley-Liss, Inc.

Stehn J.R.,University of New South Wales | Haass N.K.,Centenary Institute | Haass N.K.,University of Sydney | Haass N.K.,University of Queensland | And 22 more authors.
Cancer Research | Year: 2013

The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. © 2013 American Association for Cancer Research.

Blue G.M.,Kids Heart Research | Blue G.M.,Heart Center for Children | Blue G.M.,University of Sydney | Kirk E.P.,Sydney Childrens Hospital | And 19 more authors.
Journal of the American College of Cardiology | Year: 2014

Background Many genes have been implicated in the development of congenital heart disease (CHD). Next-generation sequencing offers opportunities for genetic testing but is often complicated by logistic and interpretative hurdles. Objectives This study sought to apply next-generation sequencing technology to CHD families with multiple affected members using a purpose-designed gene panel to assess diagnostic potential for future clinical applications. Methods We designed a targeted next-generation sequencing gene panel for 57 genes previously implicated in CHD. Probands were screened in 16 families with strong CHD histories and in 15 control subjects. Variants affecting proteincoding regions were classified in silico using prediction programs and filtered according to predicted mode of inheritance, minor allele frequencies, and presence in databases such as dbSNP (Single Nucleotide Polymorphism Database) and ESP (Exome Sequencing Project). Disease segregation studies were conducted in variants identified in CHD cases predicted to be deleterious and with minor allele frequencies <0.1%. RESULTS Thirteen potential disease-causing variants were identified in 9 families. Of these, 5 variants segregated with disease phenotype, revealing a likely molecular diagnosis in 31% of this cohort. Significant increases in the number of "indels, nonsense, and splice" variants, as well as variants classified as "probably damaging" were identified in CHD cases but not in control subjects. Also, there was a significant increase in the total number of "rare" and "low" frequency variants (minor allele frequencies <0.05) in the CHD cases. Conclusions When multiple relatives are affected by CHD, a gene panel-based approach may identify its cause in up to 31% of families. Identifying causal variants has implications for clinical care and future family planning. © 2014 by the American College of Cardiology Foundation.

Blue G.M.,Kids Heart Research | Blue G.M.,Heart Center for Children | Blue G.M.,University of Sydney | Kasparian N.A.,Heart Center for Children | And 8 more authors.
International Journal of Cardiology | Year: 2015

Background One of the key questions asked by parents of children with congenital heart disease (CHD) is 'why' and 'how did this happen?'. Receiving more information in response to these questions is therefore important to parents. This study sought to assess the efficacy of individualised genetic counselling sessions in improving knowledge of causation and psychosocial functioning in parents of children with CHD.Methods Parents of children undergoing surgery for CHD were offered individualised genetic counselling during their child's hospital admission. Assessments occurred at three time-points (immediately pre-, immediately post-, and two months post-session) using questionnaires comprising a purpose-designed knowledge measure, as well as validated psychological measures.Results Of the 94 participants approached, 57 attended the genetic counselling session (participation rate = 60.6%). Knowledge scores for the participants who completed all three questionnaires improved significantly from pre- (x¯ = 7.38/16, SD = 3.53) to post-session (x¯ = 13.33/16, SD = 2.82) (p < 0.001). Participants retained this knowledge over time, with no changes in scores at two-month follow-up (p = 0.11). Perceived personal control also increased post-session, while reported guilt, shame, depression, anxiety and stress decreased. Overall satisfaction was high, with 96.4% of participants indicating they would recommend this service to other parents of children with CHD.Conclusion Individualised genetic counselling sessions were highly beneficial to parents of children with CHD in regards to improving knowledge about the causes of CHD and enhancing psychosocial functioning, and should be considered as part of 'best care' practices. © 2014 Elsevier Ireland Ltd. All rights reserved.

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