Honorary Consultant in Clinical Genetics Northern Genetics Service Newcastle upon Tyne Hospitals NHS Foundation Trust
Cardiovascular Development and Congenital Heart Disease
Congenital heart disease (CHD) affects approximately 1% of live births and is a major source of morbidity and mortality in childhood. Whilst it can occur in the context of a chromosomal abnormality or genetic syndrome in the majority of affected children congenital heart disease is an isolated malformation. The probability of subsequent siblings (or offspring) being affected is greater than for the general population indicating a genetic component in the aetiology of cardiac malformation. My main area of research is looking for the genetic causes of cardiac malformation. I chose to focus initially on Tetralogy of Fallot which is the commonest form of cyanotic congenital heart disease, affecting approximately 3 per 10,000 newborns. TOF is fully correctable by surgery in infancy but there is substantial late morbidity, in particular from pulmonary valvular insufficiency and atrial and ventricular arrhythmias. With colleagues I have established a large collection of samples from affected individuals and their parents for TOF and other types of heart malformation. We are looking for both common and rare variants contributing to TOF using association studies, copy number variant analysis and next generation sequencing. I am also interested in gene-environment interaction in the aetiology of congenital heart disease. The environmental factor that I have chosen as the paradigm is maternal diabetes and I am keen to collaborate to increase the size of the collection of samples from affected offspring of diabetic women.
Modulation of Hedgehog signalling
My group identified EVC and EVC2 as the causative genes for Ellis-van Creveld syndrome (EvC). People with EvC have short limbs, short ribs, an extra digit, missing and abnormally shaped teeth and sometimes also have congenital heart malformations. EVC and EVC2 are novel proteins, the functions of which were unknown. We generated an Evc-/-mouse, the skeletal and orofacial abnormalities of which strikingly resemble the human disorder. Using the mouse model we have ascertained the molecular pathology underlying the EvC syndrome by demonstrating that Evc is required for Ihh signalling at the endochondral growth plate, acting at or downstream of Smo in the Ihh signalling pathway. Evc and Evc2 are transmembrane proteins that localise to primary cilia, this localisation being dependent on their interaction. My objective, in collaboration with victor Ruiz-Perez, is to elucidate the role of Evc and Evc2 in hedgehog signalling.
Goodship J, Henderson D. Cardiac development and cardiovascular malformation.
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