The concept of atrial cardiomyopathy (ACM) was initially proposed a decade ago (1) and was widely accepted until recently. According to EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies, ACM is defined as “any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations”. It's classified into four classes: principally cardiomyocyte changes, principally fibrotic changes, combined cardiomyocyte-pathology/fibrosis, and primarily non-collagen infiltration (with or without cardiomyocyte changes) (2). However, this histological-based classification system has limited practical application for most patients due to the need for an invasive atrial biopsy to confirm diagnosis. ACM is characterized by a dilated atrium with various arrhythmias (mainly atrial arrhythmias), and was found to be associated with Ebstein anomaly (3), dilated cardiomyopathy (DCM) (4), myocarditis (5), amyloidosis (6) and muscular dystrophies (7). Although its prevalence is unknown, ACM was often observed in various clinical conditions, such as isolated atrial fibrillation, diabetes, aging, smoking, heart failure, valvular disease, amyloidosis and inflammatory infiltration, etc (2, 6). The ACM could be sporadic or familial, suggesting the possibility of genetic determinants in some forms of ACM. The first case of familial atrial cardiomyopathy was described by Nagle RE et al. in 1972 (8), who described a familial syndrome almost exclusively affecting the atria and atrioventricular-conducting system, with a combination of ectopic supraventricular rhythms and atrioventricular block that eventually progressed to atrial standstill. Thereafter, additional cases of ACM with hereditary components were reported and a variety of gene mutations associated with ACM were identified, including heterozygous mutations of SCN5A (9) and GJA5 (encoding connexin 40) genes (10), the gain-of-function KCNQ1 missense variant (11), homozygous mutation in the natriuretic peptide precursor A (NPPA) gene (12), nonsense mutation in the STA Gene (13), nonsense mutation in the LMNA gene (c.475G > T) (14), missense mutation in the LMNA gene (p.R335W) (15), etc. Currently, the LMNA gene, located on chromosome 1q21.1–21.2, is thought to be one of the most common disease-associated genes for familial DCM with respects to conduction system diseases (15). As of now, a total of 498 LMNA pathogenic variants have been identified and are associated with more than 15 different phenotypes (16, 17). Here we report a novel pathogenic variant of LMNA gene, discovered to be a frame-shift mutation of the LMNA gene at c.1526del, in a large six-generation family. The clinical manifestation was ACM, including giant right atrium, sick sinus syndrome, atrial standstill, left ventricular tachycardia, and bicuspid aortic valve malformation. To the best of our knowledge, this is a novel identification of a pathogenic variant of LMNA gene. Our findings facilitate improved understanding of the LMNA mutation genotype and its clinical phenotype to other known laminopathies.

DCM is a frequent cause of heart failure and sudden cardiac death worldwide. It is now well established the significance of genetic etiology with currently more than 40 DCM genes implicated. Among them mutations on TTN gene (encoding titin which provides structure, flexibility, and stability to sarcomeres) was the largest contributor, following by LMNA gene, SCN5A and DES gene (21, 22). The LMNA gene is composed of 12 exons and encodes intermediate filament proteins lamin A and C via alternative splicing of exon 10 (23, 24). The lamin A/C proteins polymerize to form a scaffold called the nuclear lamina (NL) at the nuclear periphery, which consists of a long α-helical domain flanked by globular amino-terminal (head) and carboxy-terminal (tail) domains. Lamins first dimerize using their α-helical rod domain, then polymerize in a polar head-to-tail manner, forming protofilaments. Between three and four protofilaments associate laterally to form an intermediate filament (25, 26). Its expression pattern is not solely confined to the atria as it also exists in skeletal muscle and ventricular myocardium (23, 24). Lamin A/C possesses a key function in the stability of the nuclear envelope, chromatin organization, and DNA-repair (25). It plays a major role in transmitting mechanical signals to the nuclear core, transportation through the nuclear envelope, and regulation of transcription (27, 28). LMNA gene mutations typically present in an autosomal dominant manner and can result in a variety of phenotypes such as lipodystrophy, muscular disease, neuropathy, progeria, and cardiomyopathy (29, 30). The cardiac phenotype includes dilated cardiomyopathy, heart failure, progressive atrioventricular block (AVB), atrial fibrillation (AF), ventricular tachycardia and fibrillation (VT/VF), and SCD (16, 17, 25, 30). The most common manifestation of the cardiac phenotype is disturbance in the electrical conducting system presenting as atrioventricular block (AV-block), and both atrial and ventricular arrhythmias (31, 32). A meta-analysis by van Berlo JH et al. (31) showed that initial ECG findings in patients with the LMNA gene mutation appeared as low amplitude P-waves and PR-intervals, and 92% of patients had developed arrhythmias after age 30% and 28% received pacemaker therapy. The cardiac phenotype of the LMNA mutation can present as predominantly right-sided cardiomyopathy (15, 33). Zhang et al. (15) identified a pathogenic variant which was a missense variant in rod 2B domain (c.1003C > T p.R335W) of LMNA gene in a large Chinese family where affected members expressed clinical findings such as atrial enlargement, atrial arrhythmia, sick sinus syndrome and AV-block.

LMNA-related cardiomyopathy accounts for 5%–10% of familial DCM (31) and the clinical outcome is considerably worse for patients harboring LMNA mutations compared to those without (34, 35). Although the precise pathophysiological processes underlying the occurrence and progression of arrhythmia in patients carrying the pathogenic variant of LMNA gene remains unknown, the following mechanisms may be involved (1) decreased spontaneous action potential beat frequency, decreased pacemaker current (I-f) density, (2) prolonged action potential duration, increased L-type calcium current density, (3) delayed post-depolarizations (DADs), arrhythmias, and increased heart rate variability, (4) DADs, arrhythmias, and cessation of spontaneous discharges caused by beta-adrenergic stimulation and rapid pacing (36). Given the extremely poor prognosis of cardiomyopathy-causing in LMNA pathogenic variant carriers, early identification of affected family members is imperative. Genetic testing allows for both early identification and diagnosis of high-risk family members. If a pathogenic variant is identified in an asymptomatic individual, regular clinical cardiovascular screening (e.g., ECG) is recommended to detect the first signs of disease, which can then be managed through early intervention. If family members are not found to carry the mutation, they can be diagnosed as unaffected and do not require serial follow-up.

In this study, we identified a novel pathogenic variant in LMNA gene which has not been reported in literature thus far. This is a c.1526del (a single nucleotide deletion) located in exon 9 on chromosome 1 (HGVS: NM_170707.4, c.1526del: p.P509Lfs*39), causing a change in the open reading frame of the gene and resulting in loss-of-function of lamin A/C. The clinical manifestation of the affected members presented similarly to the pathogenic variant reported by Zhang et al. (15), but clinical symptoms of the c.1526del pathogenic variant presented earlier in life (∼20 years old). Although the patient's symptoms were nonspecific, auxiliary examination provided clues to warrant further investigation. ECG findings presented as gradual worsening of electrical conduction due to sinus bradycardia, sick sinus syndrome, AV-block, and atrial/ventricular arrhythmia progressing to eventual atrial electrical quiescence. A giant right atrium was a significant finding associated with this pathogenic variant and accompanied by RV enlargement and bicuspid aortic valve malformation. All affected members required eventual pacemaker implantation, with some possibly needing ICD implantation due to VT. Therefore, genetic screening of family members is necessary once familial inheritance is suspected as it could provide early diagnosis and treatment for the affected family members. Actually, a same site mutation of c.1526 (c.1526dup, p.Asn509fs) has been reported in ClinVar, however different from the pathogenic variant we identified which was a novel deletion mutation and presented as cardiac phenotype, this variants was seen in Charcot-Marie-Tooth disease type 2, cardiovascular phenotype was uncertain.

In summary, this study describes a novel cardiac phenotype caused by a newly identified pathogenic variant in LMNA gene (c.1526del p.P509Lfs*39) in a large family, where affected family members were clinically characterized by a giant right atrium, sick sinus syndrome, atrial/ventricular arrhythmia with progressive loss of atrial electric activity to atrial standstill, and potential accompanying bicuspid aortic valve malformation. This study expands the phenotype of the pathogenic variant in LMNA gene and also provides genetic information regarding atrial cardiomyopathy. To the best of our knowledge, this is a novel pathogenic variant first identified by our research team.