Tell me once, tell me soon: parents’ preferences for clinical genetics services for congenital heart disease

© 2018, American College of Medical Genetics and Genomics. Purpose: As the molecular basis of congenital heart disease (CHD) comes into sharper focus, cardiac genetics services are likely to play an increasingly important role. This study aimed to identify parents’ preferences for, and willingness to participate in, clinical genetics services for CHD. Methods: A discrete choice experiment was developed to assess parents’ preferences for pediatric cardiogenetics services based on four attributes: appointment format, health professionals involved, waiting time, and information format. Data were analyzed using a mixed logit model. Results: One hundred parents with a living child diagnosed with CHD requiring surgical intervention between 2000 and 2009 completed the discrete choice experiment. Parents expressed a clear preference for cardiac genetics services featuring (i) a single appointment, (ii) the presence of a clinical geneticist and a genetic counselor, (iii) both verbal (oral) and Web-based information about CHD and genetics, and (iv) availability of an appointment within 2 weeks. If offered such conditions, 93% of respondents indicated that they would attend. The choice of service was most strongly influenced by the presence of both a clinical geneticist and a genetic counselor. Conclusion: Parents of children with CHD favor a single, timely genetics appointment with both a geneticist and a genetic counselor present. If appointments offered match these preferences, uptake is likely to be high

Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

<p>Abstract</p> <p>Background</p> <p>HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns.</p> <p>Methods</p> <p>HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated.</p> <p>Results</p> <p>Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (<it>P </it>< 0.05), but was not an independent prognostic marker of survival <it>(P > 0.05)</it>. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (<it>P </it>< 0.05). The 5-year survival rate in patients with negative and positive VEGF expression was 70.2% and 61.9% respectively; the difference was not statistically significant <it>(P = 0.146)</it>. No correlation between HER-2/neu and VEGF expression was detected (<it>P = </it>0.151).</p> <p>Conclusions</p> <p>HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.</p

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.

Genetic testing has advanced significantly since the publication of the 2011 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies.1 In addition to single-gene testing, there is now the ability to perform whole-exome sequencing (WES) and whole-genome sequencing (WGS). There is growing appreciation of oligogenic disorders,2,3 the role of modifier genes,2 and the use of genetic testing for risk stratification, even in common cardiac diseases such as coronary artery disease or atrial fibrillation (AFib), including a proposal for a score awaiting validation.4 This document reviews the state of genetic testing at the present time, and addresses the questions of what tests to perform and when to perform them. It should be noted that, as articulated in a 1999 Task Force Document by the European Society of Cardiology (ESC) on the legal value of medical guidelines,5 ‘The guidelines from an international organization, such as the ESC, have no specific legal territory and have no legally enforcing character. Nonetheless, in so far as they represent the state-of-the-art, they may be used as indicating deviation from evidence-based medicine in cases of questioned liability’. In the case of potentially lethal and treatable conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS), it is the responsibility of the physician, preferably in conjunction with an expert genetics team, to communicate to the patient/family the critical importance of family screening, whether this be facilitated by cascade genetic testing or by broader clinical family screenin

Common genetic variants contribute to risk of transposition of the great arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

Health-Related Quality of Life in Children, Adolescents, and Adults With a Fontan Circulation: A Meta-Analysis.

Background People with a Fontan circulation experience a range of physical, psychosocial and neurodevelopmental challenges alongside, or caused by, their cardiac condition, with significant consequences for health-related quality of life (HRQOL). We meta-analyzed HRQOL outcomes reported by people with a Fontan circulation or their proxies and evaluated predictors of poorer HRQOL. Methods and Results Six electronic databases were searched for peer-reviewed, English-language articles published before March 2019. Standardized mean differences (SMD) were calculated using fixed and random-effects models. Fifty articles reporting on 29 unique studies capturing HRQOL outcomes for 2793 people with a Fontan circulation and 1437 parent-proxies were analyzed. HRQOL was lower in individuals with a Fontan circulation compared with healthy referents or normative samples (SMD, -0.92; 95% CI, -1.36 to -0.48; P<0.001). Lower scores were reported across all HRQOL domains, with the largest differences found for physical (SMD, -0.90; 95% CI, -1.13 to -0.67; P<0.001) and school/work functioning (SMD, -0.71; 95% CI, -0.90 to -0.52; P<0.001). Meta-regression analyses found no significant predictors of self-reported physical functioning, but older age at Fontan operation was associated with poorer emotional functioning (β=-0.124; P=0.004), and diagnosis of hypoplastic left heart was associated with poorer social functioning (β=-0.007; P=0.048). Sensitivity analyses showed use of the PedsQL Core Module was associated with lower HRQOL scores compared with the Short-Form Health Survey-36. Conclusions HRQOL outcomes for people with a Fontan circulation are lower than the general population. Optimal care acknowledges the lifelong impact of the Fontan circulation on HRQOL and offers targeted strategies to improve outcomes for this growing population

Feeding difficulties in neonates following cardiac surgery: Determinants of prolonged feeding-tube use

Aim The aims of this study were to examine the prevalence and potential correlates of feeding difficulties in infants who underwent cardiac surgery in the neonatal period and to investigate resource utilisation by infants with feeding difficulties. Methods All neonates who underwent their first cardiac surgery at the Heart Centre for Children, The Children's Hospital at Westmead, between January and December, 2009 were included. Demographic, preoperative, intraoperative, and postoperative data were collected via electronic medical records. For the purpose of this study, feeding difficulty was defined as the requirement for ongoing tube feeding at the time of discharge home or transfer to another hospital. Results Out of a total of 79 neonates, 24 (30%) were discharged home or transferred to another hospital with a feeding tube. Feeding difficulties were associated with the presence of a genetic syndrome (p<0.0001), assisted feeding preoperatively (odds ratio (OR)=4.4, p=0.03), and having a palliative procedure before biventricular repair (OR=5.1, p=0.02). Infants with feeding difficulties had significantly more reviews by speech pathologists (M=5.9, SD=7.9), dieticians (M=5.9, SD=5.4), and cardiac clinical nurse consultants (M=1.2, SD=1.4) compared with those without feeding difficulties. Conclusions This study identified factors that can be used in the early recognition of infant feeding difficulties, to help guide the direction of limited health resources, as well as being focal points for future research and clinical practice improvement

ConanVarvar: a versatile tool for the detection of large syndromic copy number variation from whole-genome sequencing data

Availibility of data and materials: The source code and test data are available online at https://github.com/VCCRI/ConanVarvar. The datasets generated and/or analysed during the current study are not publicly available due to the use of patient-identifiable clinical data, but are available from the corresponding author on reasonable request. Project name: ConanVarvar; Project home page: https://github.com/VCCRI/ConanVarvar; Docker Hub: https://hub.docker.com/r/mgud/conanvarvar; Operating systems: Platform independent; Programming languages: R; Other requirements: Docker; License: GNU GPL.Copyright © The Author(s) 2023. Background: A wide range of tools are available for the detection of copy number variants (CNVs) from whole-genome sequencing (WGS) data. However, none of them focus on clinically-relevant CNVs, such as those that are associated with known genetic syndromes. Such variants are often large in size, typically 1–5 Mb, but currently available CNV callers have been developed and benchmarked for the discovery of smaller variants. Thus, the ability of these programs to detect tens of real syndromic CNVs remains largely unknown. Results: Here we present ConanVarvar, a tool which implements a complete workflow for the targeted analysis of large germline CNVs from WGS data. ConanVarvar comes with an intuitive R Shiny graphical user interface and annotates identified variants with information about 56 associated syndromic conditions. We benchmarked ConanVarvar and four other programs on a dataset containing real and simulated syndromic CNVs larger than 1 Mb. In comparison to other tools, ConanVarvar reports 10–30 times less false-positive variants without compromising sensitivity and is quicker to run, especially on large batches of samples. Conclusions: ConanVarvar is a useful instrument for primary analysis in disease sequencing studies, where large CNVs could be the cause of disease.This work was supported by NSW State Government [S.L.D., D.S.W., E.G.], Chain Reaction (The Ultimate Corporate Bike Challenge) [S.L.D.], the NSW Health Cardiovascular Senior Scientist Grant [S.L.D.], the NSW Health Early-Mid Career Fellowship [E.G.], the National Health and Medical Research Council (Project Grant 1162878) [S.L.D., D.S.W., E.G.], the National Health and Medical Research Council Principal Research Fellowship (1135886) [S.L.D.], the National Heart Foundation of Australia Future Leader Fellowship (101204) [E.G.], the National Heart Foundation of Australia Postdoctoral Fellowship (101894) [G.M.B.], and the Office of Health and Medical Research