Rare genetic cardiovascular diseases, also called ‘inherited cardiac conditions’, when considered together affect around 1% of the population. As a group they carry a unique susceptibility to sudden death at a young age, usually occurring in otherwise healthy people. They are therefore among the most devastating of rare diseases for affected families. These conditions may affect the functioning of the heart muscle (cardiomyopathies), the regulation of the heart beat (arrhythmias) or cause weakness of major blood vessels (aortopathies). The treatments for these conditions are onerous and in themselves risky: for example the implantation of devices in the body to restart the heart in the event of a sudden cardiac arrest carries a risk of infection and the need for lifelong close followup.

Congenital heart disease, where a baby is born with a structural abnormality of the heart, remains a significant cause of childhood death, may require repeated surgical operations, and sometimes leads to ongoing ill health in adult life together with a shorter lifespan. There is a substantial genetic component to the risk of congenital heart disease. The number of adults with congenital heart disease is increasing substantially as more people with the condition survive childhood.

The lymph vessels are a part of the circulatory system of the body with roles in preventing the congestion of body tissues with fluid, and the functioning of the immune system. Genetic abnormalities of these vessels lead to severe problems with swelling of the limbs. Certain genetic conditions may affect the small blood vessels within the brain and lead to devastating strokes, often at young ages.

A substantial proportion of people with genetic cardiovascular diseases do not have the causative gene for their condition identified. Such genetic diagnoses may inform treatment options, lifestyle choices, and are particularly important in assessing the risk to family members, who otherwise may live many years with uncertainty about their own health and the health of their families.

We will work with the 100,000 Genomes Project data to provide genetic diagnoses to participants. We comprise a diverse group of people who together have expertise in all aspects of genetic cardiovascular disease, from patient care to basic laboratory science. We will harness this expertise to discover new genes in 100,000 Genomes patients, find out how those genes contribute to risk, and look for ways to use that information in best helping families to live with their inherited cardiovascular disease.

Below are the current subdomains for this domain. You can find the full details of the research proposed by this domain in the Cardiovascular detailed research plan.

ArrhythmiasElijah Behr
Andrew Grace
Clifford Garratt
Three main arrhythmia syndrome phenotypes are currently eligible for whole genome sequencing (WGS): long QT syndrome (LQTS); Brugada syndrome (BrS); and catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders predispose to sudden death from womb to adulthood and are responsible for much unexplained sudden death
CADASIL negative small vessel cerebral diseaseHugh MarkusCerebral small vessel disease is the most common stroke phenotype caused by monogenic diseases. The most common of these is CADASIL, first identified in 1994. More recently a number of other monogenic causes of cerebral SVD have been described including CARASIL, TREX1 cerebral small vessel disease, COL4A1, COL4A2.
CardiomyopathyHugh Watkins
Perry Elliott
Stuart Cook
There are three main inherited cardiomyopathy sub-types, as well as a number of other more or less discrete entities, that together comprise the most prevalent inherited cardiac conditions and indeed are some of the most common, serious inherited diseases of any system: hypertrophic cardiomyopathy (HCM); dilated cardiomyopathy (DCM); and arrhythmogenic right ventricular cardiomyopathy (ARVC).
Congenital Heart DiseaseBernard KeavneyWe will use the 100,000 Genomes project data in trios and multiplex families to identify potentially pathogenic de novo and inherited variation respectively. We will adopt genome-wide approaches but also reduce the genomic search space by referring to lists of candidate genes assembled from our domain members’ extensive knowledge of human CHD genetics, mouse models of CHD and gene networks important in heart and vascular development.
Familial hypercholesterolaemiaSteve HumphriesFamilial Hypercholesterolaemia (FH) is an autosomal dominant disorder, characterised clinically by elevated LDL-cholesterol (LDL-C) levels, and as a consequence premature mortality and morbidity from coronary heart disease (CHD). Of the roughly 240,000 FH patients predicted in the UK less than 10% have currently been identified and are being effectively treated in lipid clinics. Cascade testing using DNA information from identified FH patients is recommended by NICE as a cost effective way to increase the number of identified FH patients, but in the absence of a systematic national screening programme most remain unidentified, although the BHF have recently funded 14 FH nurses to carry this out in 11 different centres throughout England. We would therefore expect between 200-400 individuals in the entire 100,000 cohort to be carrying an identifiable FH-causing mutation that can be reported to patients and clinicians for such cascade testing and treatment through genetic services (MW, MW, ZM).
Familial thoracic aortic aneurysms and dissectionPaul CliftThoracic aortic dissection is a cause of sudden death. A significant proportion of individuals have a family history of aortic dissection consistent with an autosomal dominant pattern of inheritance. Existing genetic testing strategies can identify known mutations in around 30-40% of probands tested. Currently known mutations occur in the TGF beta and ACTIN pathways (1), and mouse genetic models of these disease have led to the development of targeted therapy using angiotensin receptor antagonists in these patient groups (2). However the majority of patients and families do not have a genetic diagnosis & these are being enrolled into the 100K Genome project.
Functional GenomicsPanos DeloukasThe development of novel bioinformatics approaches to analyse variation in the 100,000 Genomes data set is a central objective of the CV GECIP. The Functional Genomics subdomain aims to empower this endeavour through integration of multi-omic data sets that can be generated across many of the analysed patient groups for economy of scale. Based on sample availability we would prioritise the generation of metabolomics profiles followed by transcriptomics analysis - expression profiles for all protein coding genes, microRNAs and long non-coding RNAs - and DNA methylation profiling.
Primary lymphoedemaPia Ostergaard
Sahar Mansour
The lymphatic vasculature is important for fluid drainage and immune responses. Dysfunction of lymphatic vessels leads to disturbed tissue fluid balance and development of lymphoedema. The lymphatic system also contributes to immune and inflammatory responses in various other pathologies, including cancer, obesity, hypertension and atherosclerosis. The majority of lymphoedema occurs as a result of an insult to the lymphatic system by extrinsic factors, such as surgery, infection (e.g. parasitic) or radiotherapy, which is known as ‘secondary lymphoedema’. When intrinsic factors, such as genetic alterations, cause lymphoedema, it is called ‘primary lymphoedema’ (PL). This is a rare but important condition caused by abnormal development of lymph vessels or failure of lymphatic function. The resulting oedema may present at birth, later in childhood, or even in adulthood. Some forms of PL are associated with life-threatening conditions, e.g. pulmonary or intestinal lymphangiectasia as in Hennekam syndrome or acute myeloid leukaemia as in Emberger Syndrome. At present the treatment is palliative not curative, and restricted to physical measures such as compression garments. Approximately 40% of PL cases are due to an identifiable genetic cause and several sub-types can be attributed to Mendelian gene defects. To date, mutations in 20 genes have been reported to cause forms of hereditary lymphoedema.
Sudden Unexplained Death in the Young (SUDY)/Sudden Infant Death Syndrome (SIDS)Elijah BehrSudden Unexplained Death in the Young (SUDY) is a term describing unexpected and unexplained death in a previously healthy person aged 1-35 years following a negative post mortem (including toxicology).1 The definition typically requires the death to be witnessed or to have occurred within 12 hours of them last being seen alive and to have no prior recorded cardiac disease. SUDY may be the first manifestation in a person (or family) of a previously undiagnosed inherited arrhythmia syndrome (“channelopathy”); encompassing a number of cardiac conditions including long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).1 These conditions are due to mutations in genes encoding cardiac ion channel proteins. They are heterogeneous conditions, typically with an underlying structurally normal heart, and a predisposition to life-threatening ventricular arrhythmias.


1) Wilde AA, Behr ER. Genetic testing for inherited cardiac disease. Nat Rev Cardiol 2013 Oct;10(10):571-83. (Arrhythmia)
2) Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol.2015 Dec;262(12):2601-16.
3) Van Laer et al. Connective tissue disorders with vascular involvement: from gene to therapy Eur J Pediatr (2013) 172:997–1005
4) Gallo et al. Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis J Clin Invest. 2014;124(1):448–460
Priori SG, Wilde AA, Hoei M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannakeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10(12):1932-63 (SUDY)

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