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

Abstract Background The literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research. Objective To characterize the atrial phenotype and possible mechanisms in a large Chinese family with heart-hand syndrome carrying LMNA missense variant in rod 2B domain (c.1003C>T p.R335W). Methods Clinical characteristics were collected based on the pedigree investigation. Comprehensive functional analyses, including molecular dynamic simulation, cellular, and animal functional assays, determined the pathogenicity in atrial myopathy. Results In the pedigree investigation, 6/13 of the mutation carriers showed heterogeneous cardiac phenotypes, and eight carriers also had brachydactyly. In silico molecular dynamics simulations predicted increased binding energy of R335W mutant lamin A. Atrial cardiomyocytes (HL-1, hiPSC-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 A peak velocity in echocardiography, and atrial lesions under the transmission electron microscope. Conclusion The LMNA p.R335W mutation leads to a 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 to the diagnosis and treatment of cardiac laminopathy.