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Genetic Abnormalities

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darodri6's version from 2016-09-19 00:57

Cardiovascular-related Dz w/Genetic Influences

DiseaseCauseCV defectOther
Familial Hypercholesterolemiaover 1000 different mutations in the LDL receptor gene (LDLR).
-Mutations in the LDLR can lead to defects in the:
1. Trx/Transl of the protein. 2. Transport of the protein in the cell to membrane 3. Binding to LDL 4. Clustering for LDL intake 5. Recycling from endosome back to membrane
increased LDL in blood --> early coronary heart dzAutosomal Dominant
Liddle SyndromeMutations in the SCNN1B or SCNN1G genes which encode subunits of the epithelial SODIUM channel (ENaC) preventing the degradation of the protein (gain-of-function).Leads to increased sodium channels and hypertension and hypokalemia.
Symptoms appear in childhood.
Autosomal Dominant
Familial Hyperaldosteronism (type I) aka Glucocorticoid-remediable aldosteronismMutation that leads to the chimeric fusion of the 11β-hydroxylase promoter (CYP11B1 gene) to the coding region of aldosterone synthase (CYP11B2 gene).Leads to retention of sodium & HTN (and hypokalemia)Autosomal Dominant
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Connective Tissue Disorders

DiseaseCauseCV defectOther
Marfan Syndromemutations in FBN-1 that lead to this dz/syndrome by REDUCING the function or amount of fibrillin-1 (microfibrils).
*Normally, Fibrillin-1 and microfibrils sequester TGF-β (inactive) --> limits cell growth....so w/o Fibrillin-1, you have uncontrolled growth!
AORTIC ROOT ANEURYSM or DISSECTION
Also: ECTOPIC LENTIS(abnormal lens position), Tall stature (arm length > height), Arachnodactyly with joint hypermobility
Autosomal Recessive; variable expressivity, occurs in 1 in 5,000; NO gender preference; 25% cases arise from spontaneous mutations
Loeys-Dietz SyndromeLoss of function mutations in TGFBR1, TGFBR2, or SMAD3-AORTIC ANEURYSM, mitral valve prolapse, long fingers, chest wall deformities, dural ectasia, but NO ECTOPIC LENTIS
-Other: widely spaced eyes, cleft palate, BIFID UVULA scoliosis, CLUB FOOT osteoporosis
Autosomal Dominant
-Cardiac defects are MORE SEVERE than Marfan syndrome (aortic rupture at earlier age and at smaller aneurysm dimensions than Marfan syndrome).
-Dx confirmed through genetic testing
Vascular type Ehlers-Danlos SyndromeMutation in type III collagen (COL3A1 gene)Symptoms: hyperextensible skin, hypermobile joints, fragile skin prone to easy lacerations and CAN CAUSE RUPTURE of COLON or LARGE ARTERIES
Facial features: thin pinched nose, thin lips
Autosomal Dominant
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Congenital Heart Defects (most affect TRANSCRIPTION FACTORS involved in cardiac development)

Chromosomal abnormalities
DiseaseCauseCV defectOther
Trisomy 21 (aka Down Syndrome)3 COPIES of CHROMOSOME 21Cardiac: ASDs (mainly), VSDs, PDAsOther Symptoms: Dysmorphic facial features,
Short neck,
Single transverse palmar crease,
Wide gap between 1st and 2nd toe,
Cognitive delay,
Hearing loss
Trisomy 18 (aka Edwards Syndrome)3 COPIES of CHROMOSOME 18Cardiac: POLYVALVULAR HEART DZ, VSDs, AVSDs and othersOther symptoms:
Intrauterine growth retardation, low birth weight
Malformations of the brain
Intellectual disability
Microcephaly, prominent occiput
Low-set ears, rotated backwards
Small mouth and chin
Rounded plantar surface “rocker feet”
Trisomy 13 - Patau Syndrome3 COPIES of CHROMOSOME 13Cardiac: MOSTLY VSDs or DISTRIBUTION of CARDIAC POSITIONOther symptoms:
Holoprosencephaly (failure of brain development)
Cleft lip/cleft palate
Renal abnormalities
Cutaneous scalp defects
Turner Syndrome (45,X)ONLY 1 COPY of the X CHROMOSOMECardiac: BICUSPID AORTIC VALVE (most common, occurs in 30%).
-Others include; COARCTATION of AORTA, valvular aortic stenosis & mitral valve prolapse
Other symptoms:
Short stature
Webbed neck
Gonadal dysgenesis
DiGeorge SyndromeDeletion of 22q11.2
-Deletes 1.5 to 3 Mbs of chromosome 22
-Includes TBX1 gene, encodes transcription factor linked to heart development.
Cardiac: 80% HAVE CONGENITAL HEART DEFECTS; including
TETRALOGY of FALLOT, TRUNCUS ARTERIOSUS (large VSD with a single outflow tract), INTERRUPTED AORTIC ARCH
Other symptoms:
Cleft palate
Hypocalcemia
Thymic hypoplasia
Developmental delay

commonly referred to as 'CATCH 22' (Cardiac defects, Abnormal facies, T-cell deficit, Cleft palate, Hypocalcemia, 22q11.2 deletion)
Williams SyndromeDeletion of 7q11.23
-Affects the ELASTIN GENE (ELN) which most likely causes the Supravalvular Aortic Stenosis
-Deletion region includes about 17 genes
Cardiac:
-MORE COMMON IN MEN WITH THIS SYNDROME
-1/3 OF CASES ARE SUPRAVALVULAR AORTIC STENOSIS (SVAS) & PROGRESSES W/AGE
-PERIPHERAL PULMONARY ARTERY STENOSIS
Other symptoms:
Learning disability with “cocktail party” behavior

Dysmorphic features:
malar flattening,
periobital fullness
heavy sagging cheeks,
short nose,
poorly developed cupid’s bow on upper lip
Noonan SyndromeMutations in PTPN11, SOS1 or RAF1 (encode proteins involved in developmental pathways)

-Autosomal Dominant
Cardiac: MOST COMMON IS PULMONARY VALVE STENOSIS, can also have HYPERTROPHIC CARDIOMYOPATHYAppears similar to Turner syndrome
this syndrome = right-sided heart defects
Turner = left-sided heart defects

Other symptoms:
Short stature
Distinctive craniofacial features
Developmental delay
Bleeding disorders
Skeletal malformations
Alagille SyndromeCaused by mutation in JAG1 or NOTCH2 genes involved in the Notch signaling pathway which is very important for development.

-Autosomal Dominant
Cardiac: PULMONARY STENOSIS, VSDs, TETRALOGY of FALLOTOther symptoms:
-abnormalities in bile ducts leading to liver damage.
-Facial features include prominent forehead, deep-set eyes, small and pointed chin
Holt-Oram SynromeLoss-of-function mutation in TBX5, transcription factor involved in heart development.

-Autosomal dominant
Cardiac: ASD or VSD; CARDIAC CONDUCTION DZ LEADING to CASES of BRADYCARDIA or FIBRILLATIONOther symptoms:
abnormal development of upper limbs, triphalangeal thumbs, carpal bone abnormalities, short forearm
Ellis-van Creveld SyndromeLoss of function mutation in EVC or EVC2 disrupting the Sonic Hedgehog pathway

-Autosomal recessive (common in Amish population of Lancaster County, PA)
Cardiac: more than 50% have congenital heart defects. Commonly results in 'COMMON ATRIUM' = ABSENCE of INTERATRIAL SEPTUM (aka cor triloculare or 3 chambered heart) due to failure of formation of septum primum and secundum; AV CANAL DEFECT; ASD; VSD)Other symptoms:
Dwarfism, polydactyly, abnormal hair and nails, dental abnormalities
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Cardiomyopathies

DiseaseCauseCV defectOther
Dilated CardiomyopathyAssociated Genes:
-Β-myosin heavy chain (MYH7)
-Lamin A/C (LMNA)
-Dystrophin (DMD)
its in the nameDilated cardiomyopathies can also be seen with mitochondrial conditions, metabolic and other disorders. THEREFORE, DCM can FOLLOW ALL TYPES of INHERITANCE PATTERNS
Muscular DystrophyX-linked RECESSIVE DISORDER
Mutations in the DMD gene encoding DYSTROPHIN
Two subtypes: Duchenne & Becker
Duchenne Muscular DystrophyX-linked RECESSIVE DISORDER
-Mutations in the DMD gene encoding DYSTROPHIN
-results in deletion of exons 45-54 --> truncated dystrophin
cardiac: 95% of THESE PATIENTS HAVE SOME CARDIAC DZ (CARDIOMYOPATHY (DILATED), EKG ABNORMALITIES, etc...)-elevated CREATINE KINASE levels in plasma (>1,000U/L in boys). Official dx via genetic testing.

Other symptoms:
Delayed motor skill development (walk at 18 months), unstable gait, mean age of diagnosis is 4 years old, use gower maneuver to stand
Hypertrophic CardiomyopathyAssociated Genes:
-Β-myosin heavy chain (MYH7)
-Myosin binding protein C (MYBPC3)
-Troponin I (TNNI3)
-Troponin T (TNNT2)

Loss of function or missense mutations can lead to this disease.
its in the name
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Heritable Arrhythmias (aka Channelopathies)

DiseaseCauseCV defectOther
Long QT SyndromeMutations in genes encoding proteins for ION CHANNELS.
Genes: KCNQ1, KCNH2, SCN5A

-Autosomal dominant
cardiac: "associated with prolonged ventricular repolarization"
Short QT SyndromeMutations in genes encoding POTASSIUM CHANNEL PROTEINS
-Genes: KCNQ1, KCNH2, KCNJ2, (encode potassium channel proteins)
-Autosomal dominant
cardiac: "shortened ventricular repolarizaton" (leads to dizziness, syncope, cardiac arrest, death)
Wolff-Parkinson-White SyndromeGenes: PRKAG2 encodes AMP-activated protein kinase (AMPK)Cardiac: Widened QRS with DELTA Wavevery common in Chinese population
Sick Sinus Syndrome-Genes: SCN5A (Na+ channel protein) and HCN4 (K+ channel protein) are the most common mutations

-Polymorphisms in MYH6 which encodes cardiac α-myosin heavy chain may increase the chance of developing this syndrome.
Cardiac: “Intrinsic SA node dysfunction that causes inappropriate bradycardia”

Symptoms: dizziness, confusion, or syncope
Catecholaminergic polymorphic ventricular tachycardia (CPVT)Mutations involve intracellular CALCIUM handling.

Genes:
RYR2 (most common) encodes ryanodine receptor which form calcium channels (autosomal dominant); and

CASQ2 which encodes calsequestrin 2 involved in storage and transport of calcium (autosomal recessive).
Cardiac: Arrhythmia induced by exercise or “emotional arousal” by delayed after depolarizations
Brugada SyndromeCaused by mutations in SCN5A gene encoding SODIUM channel subunit.

-Autosomal dominant
Cardiac: “prominent ST elevation in leads V1-V3”More common in Asian population

It has been determined that it is the same disease as Sudden unexplained nocturnal death syndrome (SUNDS) which was originally linked to the SE Asian population.
Mutations in SCNA5 geneMUTATIONS IN (THIS GENE) GIVE A BROAD VARIABLE ARRAY OF PHENOTYPESDifferent mutations in this gene can cause Brugada syndrome, LQT3 (Long QT Syndrome), and progressive cardiac conduction defectThe phenotypic difference in these disorders are very small and may not be distinguishable
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