Cardiovascular Genetic Disorders Flashcards
Name the genetic forms of cardiomyopathy.
HCM ARVC/D LVNC Glycogen storage (PRKAG2; Danon) conduction defects mitochondrial myopathies ion channel disorders
What are the general guidelines for assessing cardiomyopathy?
3 generation family history
clinical screening (pathogenic variant carriers vs unknown pathogenic variant)
genetic testing of most clearly affected family member (best- HCM, ARVD; okay- DCM; not great- LVNC, RCM)
genetic counseling
What is hypertrophic cardiomyopathy?
massively thickened heart muscles resulting in obstruction of outflow, poor filling of the heart in diastoly causing dyspnea, and sudden death via ventricular tachycardia
What factors make genetic testing for familial HCM most efficient?
positive family history (60%)
LV wall thickness greater than 25mm (50%)
Age at diagnosis less than 25 years (50%)
Describe the inheritance of Familial Hypertrophic Cardiomyopathy.
AD with incomplete and age dependent penetrance
mutations normally in MBPC3 and MYH4
de novo in ~1/3
Describe Fabry disease.
X linked with affected females (rare)
phenotype including HCM can be treated with ERT
Describe the genotype-phenotype correlation in HCM.
variable due to multiple pathogenic variants, modifying genes, and environmental factors
sarcomeric gene mutations present with worse phenotype than other mutations (earlier age at presentation, greater chance of family history of HCM and SCD, and greater LVWT)
Describe Romano-Ward syndrome.
AD Long QT syndrome
prolonged QT and sudden death without hearing changes
caused by mutations in KCNQ1 and KCNH2 (HERG) genes most commonly
Describe Jervel and Lang-Nielsen syndrome.
AR Long QT Syndrome
prolonged QT and sudden death
often associated with congenital deafness
caused by mutations in KCNQ1 and KCNE1 (Mink) most commonly
List the kinds of Long QT syndrome and the precipitating factors of cardiac events.
Long QT1- physical exercise (especially swimming)
Long QT2- auditory stimuli (especially alarms or jump scares)
Long QT3- sleep or rest arousal
Describe what treatments to use per the kind of Long QT syndrome.
LQT3- use pace maker (beta blockers are NOT effective)
LQT2- beta blockers somewhat effective
LQT1- beta blockers protective
What is Brugada syndrome?
AD associated with SCN5A mostly
low penetrance (20%)
also called SUDS in Asia (where most prevalent)
presents with ST elevation in precordial leads (often with apparent R bundle branch blockage and transiently normalizing ECG) and life threatening arrhythmias (acute)
What is Marfan syndrome?
aortopathy
AD with complete penetrance mostly due to FBN1 mutations
presents with positive thumb and wrist signs, mitral valve regurgitation, ectopic lentis (upward), pectus deformity, aortic aneurysm and disection, arachnodactly/ dolichostenomelia, dural ectasia (with sciatica), and skeletal myopathy
What is the Ghent critreia?
diagnosis of Marfan syndrome
If Fhx is negative you must have 2+ of the following:
ectopia lentis
systemic score of >7
FBN1 mutation
If Fhx is positive you must have 1+ of the following:
ectopia lentis
systemic score >7
aortic root z score >2 for ages >20 years (>3 for ages <20 years)
How is Marfan syndrome managed?
surgical intervention (aortic root replacement/ David procedure) at 5cm dilation or prior to pregnancy in women medical management (beta blockers)
What is Beal syndrome?
similar to Marfan syndrome
no ectopia lentis
mutations in FBN2 gene
What is Neonatal Marfan syndrome?
presents in infancy with much more severe phenotype and multiple complications
clearly dysmorphic
often heart failure due to valvular regurgitation
50% 1 year survival
due to alterations in exons 25-32 of the FBN1 gene
What conditions have overlapping phenotypes with Marfan syndrome?
MASS phenotype Familial aortic aneurysm homocystenuria Ehlers-Danlose Loeyz-Dietz syndrome
What is MASS phenotype?
Myopia, Mitral valve prolapse, mild Aortic dilation, Striae, Skeletal
AD
caused by FBN1 haploinsufficiency
beta blockers not appropriate
What is Familial Aortic Aneurysm?
AD
normal phenotype
some caused by FBN1 pathogenic variants
beta blockers appropriate
What is homocystenuria?
AR
Marfanoid appearance, ID, malar flush, thromboses, subluxation of lense downward
diagnosed by urine and serum amino acids
What is Ehlers-Danlose?
bowel and arterial ruptures
small joint hypermobility
diagnosed by COL3A1 gene
What are features of Loeys-Dietz Syndrome?
Marfanoid appearance
hypertelorism
arterial tortuosity
bifid uvula
What are the features of Loeys-Dietz Type II?
aortic root aneurysm arterial tortuosity translucent or velvety skin atrophic scars joint laxity
What is the genetic etiology of Loeys-Dietz syndrome?
TGFBR1 and 2 mostly (encodes for TGF beta receptors)
SMAD2
TGFB2
How is Loeys-Dietz syndrome diagnosed?
pathogenic varient on genetic testing
+ aortic root dilation
+ other compatible systemic features
