Genomic coordinate (human 10:119,651,380 BAG3) & (mouse 7:128,125,340 Bag3).
Cytoband (human 10q26.11 BAG3) & (mouse 7qF3 Bag3).
Here I present: “Autosomal-dominant Dilated-cardiomyopathy“, Victor McKusick, Mendelian Inheritance in Man’, 1966. (BAG3) icd10=I42.0
INTRODUCTION.
Autosomal-dominant Dilated Cardiomyopathy.
Definition: Dilated cardiomyopathy (DCM) is characterized by dilation of the left (and often right) ventricle with reduced systolic function, not explained by abnormal loading conditions or coronary artery disease. In autosomal-dominant DCM, a single pathogenic variant is sufficient to cause disease, with vertical transmission across generations.
Genetics:
Inheritance: Autosomal dominant
Penetrance: Often age-dependent and incomplete
Expressivity: Highly variable—even within the same family
Common causative genes
TTN (titin; truncating variants most common)
LMNA (lamin A/C) – high arrhythmia risk
MYH7, TNNT2, TNNI3 (sarcomeric)
DSP, FLNC, DES (cytoskeletal/desmosomal)
RBM20, BAG3, PLN
Genotype–phenotype note:
LMNA and FLNC variants are associated with early conduction disease, malignant ventricular arrhythmias, and may warrant earlier ICD consideration.
Pathophysiology
Impaired force generation or transmission (sarcomere/cytoskeleton)
Defective mechanosensing and nuclear integrity (e.g., LMNA)
Progressive ventricular remodeling → dilation, fibrosis, systolic failure
Electrical instability → atrial/ventricular arrhythmias
Clinical Features:
Symptoms: Dyspnea, fatigue, edema, exercise intolerance
Arrhythmias: Atrial fibrillation, ventricular tachyarrhythmias
Conduction disease: AV block, bundle branch block (gene-dependent)
Complications: Heart failure, thromboembolism, sudden cardiac death
Diagnosis:
Echocardiography: Dilated LV, reduced LVEF
Cardiac MRI: Fibrosis (late gadolinium enhancement) for risk stratification
ECG/Holter: Conduction disease, arrhythmias
Genetic testing: Multigene panel when familial disease suspected
Family screening: First-degree relatives (echo + ECG), repeated over time
Management:
Heart failure therapy (guideline-directed):
ACEi/ARB/ARNI, β-blocker, MRA, SGLT2 inhibitor
Diuretics for congestion
Arrhythmia & device therapy:
ICD: Primary prevention in selected high-risk genotypes (e.g., LMNA) even at modest LVEF reduction
CRT: If dyssynchrony criteria met
Anticoagulation when indicated (e.g., AF)
Advanced therapies:
LVAD, heart transplantation for end-stage disease
Prognosis:
Variable; influenced by gene, fibrosis burden, arrhythmias, and response to therapy
Early genetic diagnosis improves surveillance and preventive care
Family & Counseling:
Cascade testing for relatives
Reproductive counseling (50% transmission risk)
Lifestyle guidance: avoid cardiotoxic exposures; tailored exercise advice.
There is evidence that autosomal-dominant dilated-cardiomyopathy is caused by mutation in the BAG-family molecular-chaperone regulator-3 (BAG3) gene encoded on genomic coordinate 10:119,651,380 and cytoband 10q26.11 in humans.
The BAG-family molecular-chaperone regulator-3 is a protein that in humans is encoded by the BAG3 which is involved in chaperone assisted selective autophagy.
