Familial atrial myopathy in a large multigenerational heart-hand syndrome pedigree carrying an LMNA missense variant in rod 2B domain (p.R335W).

Background: The literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research.
Objective: The purpose of this study was to characterize the atrial phenotypes and possible mechanisms in a large Chinese family with heart-hand syndrome carrying a LMNA missense variant in rod 2B domain (c.1003C>T p.R335W).
Methods: Clinical characteristics were collected on the basis of the pedigree investigation. Comprehensive functional analyses, including molecular dynamic (MD) simulation, cellular, and animal functional assays, determined the pathogenicity in atrial myopathy.
Results: In the pedigree investigation, 6 of 13 of the mutation carriers showed heterogeneous cardiac phenotypes and 8 carriers also had brachydactyly. In silico molecular dynamics simulations predicted increased binding energy of the R335W mutant lamin A. Atrial cardiomyocytes (HL-1, human induced pluripotent stem cell-derived atrial cardiomyocytes) expressing R335W showed abnormal nuclear morphology, compromised DNA repair, and dysfunctional contraction. Adult zebrafish expressing mutant lamin A showed increased P wave duration in the electrocardiogram, decreased peak A wave velocity in echocardiography, and atrial lesions under the transmission electron microscope.
Conclusion: LMNA p.R335W mutation leads to familial heart-hand syndrome characterized by an overlapping phenotype of prominent atrial lesions and brachydactyly. The unstable lamin dimerization and impaired DNA repair are possible mechanisms underlying cardiac phenotypes. Our findings consolidated the genetic role in the course of atrial arrhythmias and cardiac aging, which is helpful in the diagnosis and treatment of cardiac laminopathy.
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