Lamin A/C -Related Cardiac Disease

Abstract

T he LMNA gene encodes for the intermediate filament proteins lamin A and C. LMNA mutations are associated with a wide spectrum of phenotypes ranging from progeroid syndromes, muscular disease, and lipodystrophy to isolated cardiac disease (dilated cardiomyopathy [DCM] and conduction disorders) and phenotypes consisting of combinations of these different features.1 Although their precise role is unknown, LMNA proteins are believed to play an important role in the structural integrity of the cell nucleus and in gene regulation. 2LMNA is one of the genes most frequently involved in genotyped DCM.3 Sinus node dysfunction, atrioventricular conduction disorders, and supraventricular and ventricular arrhythmias often precede or accompany DCM.4 LMNArelated cardiac disease is associated with a high incidence of major cardiac events like sudden cardiac death, appropriate implantable cardioverter-defibrillator (ICD) therapy, or endstage heart failure. DCM patients with an LMNA mutation are, in general, believed to have a poor prognosis compared with non-LMNA mutation DCM patients. 5,6 Currently, with all the new DNA-sequencing technologies implemented in routine patient care, increasing numbers Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membranepermeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p. (Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations b...

LMNA Mutations Associated With Mild and Late-Onset Phenotype

“…In fact, mutation carriers shared a 1 Mb haplotype around the LMNA gene, with a combined LOD score of 3.46, suggesting a common founder. 12 The p.(Arg331Gln) mutation has been previously reported in 3 patients. One case was in Italy and was associated with late-onset DCM associated with conduction disease phenotype.…”

“…The detection rate of genetic variants and mutations is faster than any functional study unraveling the functional role of each identified variant. Beyond in silico analysis that predicts, but does not demonstrate, the effects of the mutation/variant in the protein, immunohistochemical and electron microscopic studies of endomyocardial biopsy tissue may also uncover the effects of 13 Experimental studies, including in vitro studies of cellular models as reported by Hoorntje et al 12 or experimental animal models, 15 can help identify potential functional effects of each given variant. However, these studies may be time-consuming, expensive, and complex, and usually test 1 variant/mutation rather than the complex genetic makeup of each single patient.…”

“…In their series, Hoorntje et al 12 describe the case of a patient (F-II-1, Family F) who was a carrier of the LMNA p.(Arg331Gln) mutation and SCN5A mutation p.(Gly1319Val). The former was likely inherited from the father, who had no DCM, experienced gastric cancer and died of ischemic heart disease.…”

“…The latter was inherited from the mother, who demonstrated a late-onset (67 years) arrhythmogenic phenotype (±18 000 PVCs per 24 hours) with mild left ventricular involvement (cardiac magnetic resonance; left ventricular ejection fraction 46%). 12 Given that the SCN5A mutation is reported as likely pathogenic (https://www.ncbi.nlm. nih.gov/clinvar/variation/67838/), but its effect when present as isolated defect seems to be clinically mild, the combination of the LMNA and SCN5A mutations likely contributes to the phenotype observed in the proband of the family (F-II-1).…”

“…This example demonstrates how the genotype segregation study in families is critical to understanding the genotype-phenotype correlations in families. 12 In addition, mutations that do not segregate at baseline family screening may demonstrate agerelated penetrance, and the segregation may become manifest during long-term follow-up ( Figure). The age-dependent manifestation of clinical traits in cardiolaminopathies underscores the importance of regular surveillance.…”