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Published on: January 16, 2019
Missense and Non-Missense Lamin A/C Gene Mutations Are Similarly Associated with Major Arrhythmic Cardiac Events: A
Cinzia Forleo1, Maria Cristina Carella1,2, Paolo Basile1,2
1Cardiology Unit, Interdisciplinary Department of Medicine (DIM), University of Bari "Aldo Moro", University Hospital Consortium Polyclinic of Bari, Piazza G. Cesare 11, 70124 Bari, Italy.
Insights
LMNA-related cardiomyopathy risk stratification may need to consider missense mutations. This study found no significant difference in major adverse cardiovascular events between missense and non-missense LMNA mutations, suggesting some missense variants warrant further investigation for sudden cardiac death risk.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Lamin A/C gene (LMNA)-related cardiomyopathy affects clinical decisions, particularly regarding implantable cardioverter defibrillators (ICDs) for malignant ventricular arrhythmia (MVA) risk.
- Current risk scores include non-missense LMNA mutations, but their established role in sudden cardiac death (SCD) is debated.
- Understanding gene-phenotype correlations is crucial for accurate prognostic implications of different LMNA mutation types.
Purpose of the Study:
- To investigate cardiac features and gene-phenotype correlations in LMNA mutant patients.
- To evaluate the prognostic implications of non-missense versus missense LMNA mutations.
- To contribute evidence for refining SCD risk stratification strategies in LMNA-related cardiomyopathy.
Main Methods:
- An observational, prospective study enrolled 54 patients with Lamin A/C mutations.
- Detailed analysis of mutation types (missense, non-frameshift insertions, frameshift deletions, nonsense) was performed.
- Follow-up assessed major adverse cardiovascular events (MACE), including death and heart transplantation.
Main Results:
- The cohort median age at first manifestation was 41 years, with a median follow-up of 8 years.
- Missense mutations were found in 48% of patients, non-frameshift insertions in 30%, frameshift deletions in 9%, and nonsense in 13%.
- No statistically significant difference in MACE prevalence (35% in missense group) was observed between missense and non-missense mutation groups (p=0.847).
Conclusions:
- The study suggests that current risk stratification models for LMNA-related cardiomyopathy may need re-evaluation.
- Certain missense LMNA mutations might warrant increased attention for their potential role in SCD risk.
- Further research is needed to clarify the prognostic significance of specific missense mutations in clinical settings.
Abstract:
Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.
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