Cardiovascular Genetics Flashcards
stretching of the muscles in the left ventricle resulting in it becoming thinner- this can spread to the right ventricle and atria
chambers affected with this cannot pump blood efficiently (systolic dysfunction - ejection fraction <50%)
Presents with palpitations, shortness of breath, fluid retention
Increased risk for thromboembolism, heart failure and sudden cardiac death
ABSENCE of abnormal loading conditions (HTN or valve disease) or significant coronary artery disease
Dilated cardiomyopathy (DCM) Familial: caused by pathogenic variants in a variety of genes (30+ including aNKRD1, BAG3, LMNA**, MYBPC3, MYH6, MYH7, RBM20, SCN5A, TNNT2, *TTN*, etc.) or as a feature of muscular dystrophy or mitochondrial disease Non-familial: caused by infective myocarditis, drugs, alcohol, and more (many cases remain unexplained- idopathic) Panel genetic testing has a 20-40% yield **see other card for highlighted information
progressive prolongation of the PR interval
LV dilation and dysfunction
high arrhythmogenic potential
dilated cardiomyopathy
non-sustained ventricular tachycardia
skeletal muscle involvement is variable (may present with Emery-Dreifuss muscular dystrophy)
Increased blood creatine phosphokinase (CPK)
LMNA (Emery-Dreifuss muscular dystrophy is also caused by other genes)
encodes lamin A and lamin C
recommend ICD consideration
myocyte hypertrophy, myocyte disarray, interstitial fibrosis
ventricular walls thicken and stiffen
ventricle cannot adequately relax and fill with blood
absence of abnormal loading conditions (hypertension or valvular disease)
risk for ventricular arrhythmias, heart failure, thromboembolism, and sudden cardiac death
Hypertrophic cardiomyopathy (HCM) Familial: caused by sarcomere protein gene variants (>30 genes identified including ACTC1, MYBPC3, MYH7, MYL2, MYL3, PLN, TNNI3, TNNT2, TPM1) or as features of metabolic, neuromuscular, or congenital syndromes Non-familial: caused by obesity, athletic training, longstanding hypertension
What are some syndromic causes of HCM?
PRKAG2- results in glycogen storage disease of the myocardium (Wolff-Parkinson-White syndrome); can present with or without HCM
LAMP2- results in metabolic storage disease of the myocardium (Danon disease; X-linked presenting with cardiomyopathy, muscle weakness, and variable intellectual disability
GLA- results in Fabry disease; X-linked; associated with left ventricular hypertrophy, may be limited to the heart
RASopathies- ~20% of Noonan syndrome patients develop HCM
Heart failure
arrhythmias
embolic events
May be associated with LV dilation, cardiomyopathy, congenital heart disease
Left Ventricular Non-Compaction
significant genetic overlap with other cardiomyopathies
Familial- genetic mutations (ACTC1, LMNA, MYBPC3, MYH7, TAZ, TNNT2)
Acquired
*Account for about 30% of LVNC
muscle tissue in the right ventricle dies and is replaced with fibro-fatty scar tissue
progressive
disrupts the heart’s electrical signals and causes arrhythmias
premature ventricular contractions (PVCs), ventricular tachycardia (V-tach or VT)
heart palpitations
syncope
cardiac arrest
right or biventricular dilation
arrhythmogenic right ventricular cardiomyopathy (ARVC)
Genetic causes- PKP2 (most common cause of ARVC), JUP (AD ARVC and AR Naxos disease -woolly hair and palmoplantar keratoderma), DSP (AD ARVC and DCM with woolly hair, keratoderma and tooth agenesis, and AR Carvajal syndrome with DCM, woolly hair, and keratoderma)
mostly in older adults
increased myocardial stiffness with only small increases in ventricular volume on ventricular filling (normal ventricular wall thickness)
cardiac failure
arrhythmias
rapid disease progression (especially if diagnosed in children)
Restrictive Cardiomyopathy (RCM) Familial: caused by sarcomere protein genetic variants, familial amyloidosis, hereditary hemochromatosis, or as a feature of metabolic or neuromuscular syndromes Non-familial: caused by non-genetic amyloidosis, scleroderma, and more (including many that are unexplained/idiopathic)
peripheral neuropathy orthostatic hypotension digestive dysfunction carpal tunnel syndrome vitreous opacity abnormal EKG cardiomyopathy (myocardial thickening due to amyloid deposits and/or progressing to myocardial stiffness) LVEF <50% congestive heart failure
Hereditary ATTR Amyloidosis most common hereditary systemic amyloidosis (multiple forms- requires tissue biopsy with immunohistochemistry or mass spectroscopy to help diagnose and differentiate between types) TTR gene (common mutations include Val30Met in Portugal/Sweden/Japan, Val122Ile in African American/West African) AD variable, age-related penetrance
Increased total cholesterol and LDL-cholesterol
Eyelid and tendon xanthomas
High risk of coronary artery disease and MI
Familial Hypercholesterolemia
APOB, LDLR, PCSK9
AD (homozygotes have more severe, early onset disease)
Distinctive facial features (low set posteriorly rotated ears, ptosis, epicanthal folds, widely spaced downslanting palpebral fissures, and bright blue/green eyes) heart defects (ASD, pulmonary valve stenosis, hypertrophic cardiomyopathy) developmental delay short stature broad/webbed neck pectus defects cryptorchidism (males) increased risk of malignancies
Noonan Spectrum Disorders
BRAF, KRAS, PTPN11, RASA2, SOS1, MAP2K1, RAF1, RIT1
What kinds of metabolic conditions are on the Ddx when cardiomyopathy is present?
Glycogen storage diseases
Lysosomal storage diseases
What kinds of metabolic conditions are on the Ddx when cardiac arrhythmias are present?
Fatty acid oxidation disease
Organic acidemias
Glycogen storage disorders
Lysosomal storage disorders
What kinds of metabolic conditions are on the Ddx when atherosclerosis is present?
Sitoserolemia
What kinds of metabolic conditions are on the Ddx when cardiac valvular disease is present?
Mucopolysaccharidoses
craniosynostosis dysmorphic features developmental delay mitral valve prolapse and aortic root dilation/aneurysm changes in connective tissue
Shprintzen Goldberg
SKI
