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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Clinical disease presentation and ECG characteristics of LMNA mutation carriers
Laura Ollila1, Kjell Nikus2, Miia Holmström3
1Heart and Lung Centre, Helsinki University Hospital , Helsinki , Finland.
Insights
Mutations in the LMNA gene cause cardiomyopathy. Male carriers show earlier symptoms, and ECG can identify these LMNA mutation carriers, distinguishing them from other DCM patients.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Nuclear Lamina Biology
Background:
- Mutations in the LMNA gene, encoding nuclear lamina proteins A and C, are a significant cause of familial dilated cardiomyopathy (DCM), accounting for 5-8% of cases.
- Understanding the clinical spectrum of LMNA-related cardiomyopathy is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the disease onset, clinical presentation, and progression in individuals carrying LMNA gene mutations.
- To compare clinical outcomes and electrocardiographic (ECG) findings between LMNA mutation carriers and patients with idiopathic DCM.
Main Methods:
- Clinical follow-up data were collected for 27 LMNA mutation carriers and 78 patients with idiopathic DCM.
- ECG data were systematically analyzed from these patients and 20 healthy controls.
- Kaplan-Meier analysis was used to assess event-free survival.
Main Results:
- No significant difference in event-free survival was observed between LMNA mutation carriers and DCM controls.
- LMNA mutation carriers experienced atrial fibrillation at a younger age (47 vs. 57 years).
- Male LMNA mutation carriers presented with clinical manifestations approximately a decade earlier than females. Non-sustained ventricular tachycardia was detected in 78% of carriers. ECG signs of septal remodeling were highly prevalent (81%) in carriers, distinguishing them from DCM controls (21%) and healthy controls (0%).
Conclusions:
- Male LMNA mutation carriers exhibit earlier disease onset compared to females.
- ECG-evidenced septal remodeling is a sensitive and specific marker for identifying LMNA mutation carriers, differentiating them from healthy individuals and DCM patients without LMNA mutations.
Objective:
Mutations in the LMNA gene encoding lamins A and C of the nuclear lamina are a frequent cause of cardiomyopathy accounting for 5-8% of familial dilated cardiomyopathy (DCM). Our aim was to study disease onset, presentation and progression among LMNA mutation carriers.
Methods:
Clinical follow-up data from 27 LMNA mutation carriers and 78 patients with idiopathic DCM without an LMNA mutation were collected. In addition, ECG data were collected and analysed systematically from 20 healthy controls.
Results:
Kaplan-Meier analysis revealed no difference in event-free survival (death, heart transplant, resuscitation and appropriate implantable cardioverter-defibrillator therapy included as events) between LMNA mutation carriers and DCM controls (p=0.5). LMNA mutation carriers presented with atrial fibrillation at a younger age than the DCM controls (47 vs 57 years, p=0.003). Male LMNA mutation carriers presented with clinical manifestations roughly a decade earlier than females. In close follow-up non-sustained ventricular tachycardia was detected in 78% of LMNA mutation carriers. ECG signs of septal remodelling were present in 81% of the LMNA mutation carriers, 21% of the DCM controls and none of the healthy controls giving a high sensitivity and specificity for the standard ECG in distinguishing LMNA mutation carriers from patients with DCM and healthy controls.
Conclusions:
Male LMNA mutation carriers present clinical manifestations at a younger age than females. ECG septal remodelling appears to distinguish LMNA mutation carriers from healthy controls and patients with DCM without LMNA mutations.
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