Identifying novel genes that cause congenital heart disease

Complex genetic networks underlie the development of the heart. Variants in some of these genes can lead to congenital heart disease (CHD). Despite the hundreds of genes that have been identified as causing CHD in humans, they only account for a small proportion of individuals with CHD. We carried out whole exome sequencing in the largest cohort of individuals with CHD reported at the time of publication, and identified three novel genome wide significant syndromic CHD genes; CDK13, PRKD1 and CHD4. Individuals with mutations in CHD4 show neurodevelopmental disability, genital abnormalities and share some phenotypic overlap with other chromatinopathies. Mutations in PRKD1 also cause syndromic CHD, but identification of further affected individuals is required to determine if there is a consistent phenotype. Prkd1 mouse models do not have a high incidence of CHD, but this gene may be important in future work as it plays a role in cardiac hypertrophy. Individuals with mutations in CDK13 show a recognisable phenotype and the mouse model shows embryonic lethality and atrioventricular canal defects. The precise mechanism by which heterozygous mutations cause disease in humans remains unclear. The phenotypic and genotypic spectrum has been expanded by subsequent reports of individuals with mutations in CKD13. We also identify a role for inherited variants with reduced penetrance in individuals with non-syndromic CHD. This is significant, as the vast majority of individuals with CHD have non-syndromic CHD. It is an important step in understanding the potential oligogenic pathogenesis of the majority of CHD. Ultimately we aim to increase our knowledge of the genes and networks that underlie CHD, to improve diagnostic yield in individuals affected with CHD. I was able to feedback pathogenic mutations in CHD genes to participants in this study locally. Following this unbiased approach of non-targeted testing in a cohort with multiple types of CHD, will improve our knowledge of genotype phenotype correlations. We also hope that understanding more about the genes involved in cardiogenesis and CHD might have relevance for the failing heart, and development of treatments in the future too

Identifying novel genes that cause congenital heart disease

Complex genetic networks underlie the development of the heart. Variants in some of these genes can lead to congenital heart disease (CHD). Despite the hundreds of genes that have been identified as causing CHD in humans, they only account for a small proportion of individuals with CHD. We carried out whole exome sequencing in the largest cohort of individuals with CHD reported at the time of publication, and identified three novel genome wide significant syndromic CHD genes; CDK13, PRKD1 and CHD4. Individuals with mutations in CHD4 show neurodevelopmental disability, genital abnormalities and share some phenotypic overlap with other chromatinopathies. Mutations in PRKD1 also cause syndromic CHD, but identification of further affected individuals is required to determine if there is a consistent phenotype. Prkd1 mouse models do not have a high incidence of CHD, but this gene may be important in future work as it plays a role in cardiac hypertrophy. Individuals with mutations in CDK13 show a recognisable phenotype and the mouse model shows embryonic lethality and atrioventricular canal defects. The precise mechanism by which heterozygous mutations cause disease in humans remains unclear. The phenotypic and genotypic spectrum has been expanded by subsequent reports of individuals with mutations in CKD13. We also identify a role for inherited variants with reduced penetrance in individuals with non-syndromic CHD. This is significant, as the vast majority of individuals with CHD have non-syndromic CHD. It is an important step in understanding the potential oligogenic pathogenesis of the majority of CHD. Ultimately we aim to increase our knowledge of the genes and networks that underlie CHD, to improve diagnostic yield in individuals affected with CHD. I was able to feedback pathogenic mutations in CHD genes to participants in this study locally. Following this unbiased approach of non-targeted testing in a cohort with multiple types of CHD, will improve our knowledge of genotype phenotype correlations. We also hope that understanding more about the genes involved in cardiogenesis and CHD might have relevance for the failing heart, and development of treatments in the future too

Opening up the participation laboratory: the co-creation of publics and futures in upstream participation.

How to embed reflexivity in public participation in techno-science and to open it up to the agency of publics are key concerns in current debates. There is a risk that engagements become limited to “laboratory experiments,” highly controlled and foreclosed by participation experts, particularly in upstream techno-sciences. In this paper, we propose a way to open up the “participation laboratory” by engaging localized, self-assembling publics in ways that respect and mobilize their ecologies of participation. Our innovative reflexive methodology introduced participatory methods to public engagement with upstream techno-science, with the public contributing to both the content and format of the project. Reflecting on the project, we draw attention to the largely overlooked issue of temporalities of participation, and the co-production of futures and publics in participation methodologies. We argue that many public participation methodologies are underpinned by the open futures model, which imagines the future as a space of unrestrained creativity. We contrast that model with the lived futures model typical of localized publics, which respects latency of materials and processes but imposes limits on creativity. We argue that to continue being societally relevant and scientifically important, public participation methods should reconcile the open future of research with the lived futures of localized publics

Industrial constructions of publics and public knowledge: a qualitative investigation of practice in the UK chemicals industry

This is a post print version of the article. The official published version can be obtained from the link below - © 2007 by SAGE PublicationsWhile the rhetoric of public engagement is increasingly commonplace within industry, there has been little research that examines how lay knowledge is conceptualized and whether it is really used within companies. Using the chemicals sector as an example, this paper explores how companies conceive of publics and "public knowledge," and how this relates to modes of engagement/communication with them. Drawing on qualitative empirical research in four companies, we demonstrate that the public for industry are primarily conceived as "consumers" and "neighbours," having concerns that should be allayed rather than as groups with knowledge meriting engagement. We conclude by highlighting the dissonance between current advocacy of engagement and the discourses and practices prevalent within industry, and highlight the need for more realistic strategies for industry/public engagement.Funding was received from the ESRC Science in Society Programme

Cyclin‐dependent kinase 13 is indispensable for normal mouse heart development

Congenital heart disease (CHD) has an incidence of approximately 1%. Over the last decade, sequencing studies including large cohorts of individuals with CHD have begun to unravel the genetic mechanisms underpinning CHD. This includes the identification of variants in cyclin-dependent kinase 13 (CDK13), in individuals with syndromic CHD. CDK13 encodes a serine/threonine protein kinase. The cyclin partner of CDK13 is cyclin K; this complex is thought to be important in transcription and RNA processing. Pathogenic variants in CDK13 cause CDK13-related disorder in humans, characterised by intellectual disability and developmental delay, recognisable facial features, feeding difficulties and structural brain defects, with 35% of individuals having CHD. To obtain a greater understanding for the role that this essential protein kinase plays in embryonic heart development, we have analysed a presumed loss of function Cdk13 transgenic mouse model (Cdk13tm1b). The homozygous mutants were embryonically lethal in most cases by E15.5. X-gal staining showed Cdk13 expression localised to developing facial regions, heart and surrounding areas at E10.5, whereas at E12.5, it was more widely present. In the E15.5 heart, staining was seen throughout. RT-qPCR showed significant reduction in Cdk13 transcript expression in homozygous compared with WT and heterozygous hearts at E10.5 and E12.5. Detailed morphological 3D analysis of embryonic and postnatal hearts was performed using high-resolution episcopic microscopy, which affords a more detailed analysis of structures such as cardiac valve leaflets and endocardial cushions, compared with more traditional histological techniques. We show that both the homozygous and heterozygous Cdk13tm1b mutants exhibit a range of CHD, including ventricular septal defects, bicuspid aortic valve, double outlet right ventricle and atrioventricular septal defects. 100% (n = 4) of homozygous hearts displayed CHD. Differential expression was seen in Cdk13tm1b homozygous mutants for two genes known to be necessary for normal heart development. The types of defects, and the presence of CHD in heterozygous mice (17.02%, n = 8/47), are consistent with the CDK13-related disorder phenotype in humans. This study provides important insights into the effects of reduced function of CDK13 in the mouse heart and contributes to our understanding of the mechanism behind this disorder as a cause of CHD

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes—CDK13, PRKD1, and CHD4, in patients with syndromic CHD. PRKD1 encodes a serine/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in PRKD1 may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a Prkd1 transgenic mouse model (Prkd1 em1 ) carrying deletion of exon 2, causing loss of function. High‐resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of Prkd1 in both normal cardiac development and CHD. We show that homozygous deletion of Prkd1 is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of Prkd1 heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT‐qPCR and western immunoblotting, respectively. A significant reduction in Prkd1 mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related Prkd2 and Prkd3 at transcript level, as evidenced by RT‐qPCR. Overall, we demonstrate a vital role of Prkd1 in heart development and the aetiology of CHD