Abstract Body (Do not enter title and authors here): Background
Pathogenic variants in the LMNA gene are associated with highly penetrant cardiomyopathy (CM), with most patients expressing the phenotype by the fourth decade. Those with LMNA variants are at increased risk of conduction defects or arrhythmia regardless of ejection fraction. Increased availability of genome sequencing enables discovery of LMNA variants in apparently asymptomatic individuals, yet data are lacking regarding the phenotypic expression profile to guide clinical management in this genome-first scenario.
Aims
Characterize the clinical spectrum of LMNA phenotypes following genome screening-based identification to inform management and risk stratification.
Methods
We screened 175,500 patient-participants with exome sequencing data in the Geisinger MyCode cohort, a healthcare-based population biobank in Pennsylvania, and identified 24 participants with pathogenic LMNA variants. These results have been disclosed to eligible participants through the MyCode Genomic Screening and Counseling program and referrals to genetic counseling and cardiology were recommended. From manual chart review, we abstracted: age, sex, variant consequence, lifetime cardiovascular symptoms, prior TTE, EKG and Holter data, interventions (e.g. permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) placement), and family history. Malignant arrythmia risk was calculated using an online risk assessment tool.
Results
Of the 24, 92% (n=22) were unaware of their variant. The median age at result disclosure was 57 years (IQR: 35-66) with 10/24 (42%) > 60 years. The most common symptoms were presyncope (58%) and palpitations (50%). Of the 24 patients, 21 had EKG or Holter data. AV Block of any degree was seen in 12/21 (57%), and 9 of the 12 (75%) received a PPM or ICD. Of the 19 patients with a TTE, 7 (37%) had an LVEF < 50%. Complete data for LMNA risk assessment was available for 17 patients, and 9 (53%) met ACC/AHA/HRS criteria for primary prevention of sudden cardiac death. Evaluation by a genetic counselor was completed in 15/24 (63%). Among the 21 patients with complete data, 10 (48%) showed a family of history of PPM/ICD, and 10 (48%) had a history of heart failure.
Conclusions
Individuals with a LMNA variant identified through genome screening had high rates of cardiac dysfunction and arrhythmia consistent with clinically ascertained cohorts. These results emphasize the value of genomic screening for the identification of LMNA-associated CM.