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Relevant diseases: - Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Dilated cardiomyopathy - Dilated cardiomyopathy and conduction defects
Inclusion Criteria
- Patients with a clear diagnosis and at least one affected relative , OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.
Exclusion Criteria
- Unclear diagnosis or history suggestive of a non-genetic cause
Prior Genetic Testing
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing. PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.
Genes
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - ARVC - PKP2 - DSP - DSG2 - DSC2
Closing Statement
These requirements will be kept under continual review during the main programme and may be subject to change.
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Cardiomyopathy
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of abnormal loading conditions (hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment. Right ventricular dilation and dysfunction may be present but are not necessary for the diagnosis.
Left ventricular noncompaction cardiomyopathy
Left ventricular non-compaction (LVNC) is characterized by prominent left ventricular trabeculae and deep inter-trabecular recesses. The myocardial wall is often thickened with a thin, compacted epicardial layer and a thickened endocardial layer. In some patients, LVNC is associated with left ventricular dilatation and systolic dysfunction, which can be transient in neonates. Comment: Left ventricular noncompaction cardiomyopathy (LVNC), also known as spongy myocardium, is a distinct form of cardiomyopathy occurring in-utero when segments of spongy myocardium fail to transform into compact, mature musculature resulting in prominent myocardial trabeculae, deep intra-trabecular recesses, and decreased cardiac function. It has been proposed that LVNC results from arrest of the compaction process during the second month of embryological development.
Right ventricular cardiomyopathy
Right ventricular dysfunction (global or regional) with functional and morphological right ventricular abnormalities, with or without left ventricular disease. Comment: This feature is most often seen in the disease arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is defined histologically by the presence of progressive replacement of right ventricular myocardium with adipose and fibrous tissue often confined to a triangle of dysplasia comprising the right ventricular inflow, outflow, and apex. While these pathologic abnormalities can result in functional and morphological right ventricular abnormalities, they also occur in the left ventricle, producing a DCM phenotype, or can be present in the absence of clinically detectable structural changes in either ventricle. For the purposes of this classification, ARVC is defined by the presence of right ventricular dysfunction (global or regional), with or without left ventricular disease, in the presence of histological evidence for the disease and/or electrocardiographic abnormalities in accordance with published criteria.
Restrictive cardiomyopathy
Restrictive left ventricular physiology is characterized by a pattern of ventricular filling in which increased stiffness of the myocardium causes ventricular pressure to rise precipitously with only small increases in volume, defined as restrictive ventricular physiology in the presence of normal or reduced diastolic volumes (of one or both ventricles), normal or reduced systolic volumes, and normal ventricular wall thickness. Comment: Historically, systolic function was said to be preserved in RCM, but is rare for contractility to be truly normal. Restrictive physiology can occur in patients with end-stage hypertrophic and DCM.
Arrhythmia
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Hypertension
The presence of chronic increased pressure in the systemic arterial system. Comment: Hypertension is sustained elevation of resting systolic BP (140 mm Hg or higher), diastolic BP (90 mm Hg or higher), or both.
Congestive heart failure
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Stroke
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Syncope
Syncope refers to a generalized weakness of muscles with loss of postural tone, inability to stand upright, and loss of consciousness. Once the patient is in a horizontal position, blood flow to the brain is no longer hindered by gravitation and consciousness is regained. Unconsciousness usually lasts for seconds to minutes. Headache and drowsiness (which usually follow seizures) do not follow a syncopal attack. Syncope results from a sudden impairment of brain metabolism usually due to a reduction in cerebral blood flow.
Sudden cardiac death
The heart suddenly and unexpectedly stops beating resulting in death within a short time period (generally within 1 h of symptom onset).
Angina pectoris
Paroxysmal chest pain that occurs with exertion or stress and is related to myocardial ischemia.
Palpitations
A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.
Edema of the lower limbs
An abnormal accumulation of fluid beneath the skin of the legs.
Dyspnea
Difficult or labored breathing.
Failure to thrive
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. Comment: Although there is no clear consensus on the exact definition of FTT, it is usually diagnoses in a child growing below the 3rd percentile or in a child whose decreased growth has cross two major growth percentiles (for example, from above the 75th percentile to below the 25th percentile).
Skeletal myopathy
Visual impairment
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Hearing impairment
A decreased magnitude of the sensory perception of sound. Comment: Hearing loss can be categorized by which part of the auditory system is damaged, as conductive hearing loss, sensorineural hearing loss, and mixed hearing loss. Another axis of classification uses the degree of hearing impairment. The degree of hearing loss is computed by using a three frequency average taken at 500 Hz, 1,000 Hz and 2,000 Hz. The average of these three frequencies is called the Pure Tone Average (PTA). 0-20 dB is considered normal, 21-40 dB mild loss, 41-60 dB moderate loss, 61-70 dB moderately severe loss,71-90 dB severe loss, and greater than 90 dB profound loss. Note that the word deafness is occasionally used to describe partial hearing loss. The World Health Organization uses the word deafness to refer to complete loss of the ability to hear, and hearing impairment to refer to any degree of reduced hearing.
Diabetes mellitus
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Intellectual disability
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70. Comment: This term should be used for children at least five years old. For younger children, consider the term Global developmental delay (HP:0001263).
Increased nuchal translucency
The presence of an abnormally large hypoechoic space in the posterior fetal neck (usually detected on prenatal ultrasound examination). Comment: Increased nuchal translucency may be related to a cystic hygroma or to mesenchymal edema. Increased nuchal translucency can be classified into three categories: 1) cardiac abnormalities, combined with abnormal ductus venosus flow velocities, is found, leading to the theory that cardiac failure causes nuchal translucency enlargement; 2) various types of abnormalities are found in the extracellular matrix of the nuchal skin of fetuses with increased nuchal translucency; 3) abnormal lymphatic development is demonstrated in fetuses with increased nuchal translucency.
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- Blood pressure
- ECG diagnostics
Cardiac measurements made using electrocardiography
- Echocardiogram
Applicable to all echocardiograms, i.e. cardiomyopathy and CTD
- Cardiac MRI
- Holter monitor test
- Doppler Diastolic function assessment
- Exercise status
- Alcohol intake
- Exercise test
- Smoking status