Cardiomyopathies

Question 1

What are syndromic causes of HCM?

Answer 1

Fabry disease (GLA gene, X-linked)
* Periodic pain crises, angiokeratomas, hypohydrosis, ocular
abnormalities, kidney disease

Pompe disease (GAA gene, AR)
* Poor feeding, macroglossia, motor delay/muscle weakness,
respiratory difficulty

RASopathies (ex. Noonan syndrome, AD)
* Characteristic facial features, short stature, developmental
delay, webbed neck

Question 2

What are non-syndromic causes of HCM?

Answer 2

Generally caused by pathogenic variants in sarcomeric genes
(~30 identified)

• Positive Fhx of HCM: ~50-60% detection rate
• No Fhx of HCM: ~20-30% detection rate
• Typically autosomal dominant
• Potential for multiple genetic variants
  * May be associated with other types of cardiomyopathy
• MYBPC3 pathogenic variants account for ~50%
• MYH7 pathogenic variants account for ~33%

Question 3

What are the most common TTR variants in hATTR?

Answer 3

p.Val50Met (Most widely studied TTR variant) and p.Val142Ile (~3.0-3.9% frequency in African American population)

Question 4

What are syndromic causes of DCM?

Answer 4

Duchenne & Becker muscular dystrophy
(DMD gene, X-linked)
* Muscle weakness, elevated serum CK, loss of ambulation in
males
* Risk for isolated DCM in heterozygous females

Carvajal syndrome (DSP gene, AR)
* Woolly hair, palmoplantar keratoderma

Barth syndrome (TAFAZZIN gene, X-linked)
* Neutropenia, muscle weakness, growth delay, infantile/early-
childhood onset

..and others! (including mitochondrial)

Question 5

What are non-syndromic causes of DCM?

Answer 5

Over 30 relevant genes identified

• Pathogenic/LP variants ~30% detection rate
• Typically autosomal dominant
• TTN pathogenic variants account for ~15-20%
  * Truncating variants
• LMNA pathogenic variants account for ~6%
• MYH7 pathogenic variants account for ~4%
• FLNC, BAG3, TNNT2, RBM20, SCN51, DES, PLN, and more..

Question 6

LMNA-related cardiomyopathy

Answer 6

LMNA gene -> Lamin A & Lamin C protein
 Intermediate filament proteins: cell strength and stability
 Autosomal dominant inheritance
 Onset generally early/mid-adulthood
 Conduction system disease and/or arrhythmias almost always precedes DCM, often before heart failure
 Usually begins as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block
 Risk for lethal arrhythmias -> consider implantable cardioverter defibrillator (ICD) implantation before EF falls below 35%
in the setting of established/known risk for arrhythmia
 May also manifest symptoms of skeletal myopathy
 Elevated serum creatine kinase

Question 7

What are common genetic causes of ARVC?

Answer 7

PKP2 (~34-74% of ACM)
 Possibly higher risk for ventricular tachycardia
 DSP (~2-39% of ACM)
Possibly higher risk for left ventricular dysfunction
 DSC2, DSG2, JUP, TMEM43

Less common genetic causes: CTNNA3, DES, LMNA, PLN, RYR2, TGFB3, TTN

Question 8

What is the mode of inheritance and penetrance of ARVC?

Answer 8

Typically autosomal dominant inheritance

Relatively low penetrance for ventricular arrhythmias

Question 9

What are family hx questions to ask about cardiomyopathies/arrhythmias?

Answer 9

FAMILY HISTORY QUESTIONS
 Arrhythmia?
 Cardiomyopathy?
 Related symptoms/medical history? (fainting, had a pacemaker or ICD)
 Heart attack/sudden cardiac death?
 Absence of coronary artery disease?
 Unexpected or unexplained death?
 Car accident, drowning – could it have been due to a cardiovascular event?
 SIDS, or sudden death in a young (otherwise heathy) person

 Consider…
 Age at diagnosis/symptom onset
 Age at death
 Any genetic testing done in the family? When?
 Reduced penetrance & variable expressivity