Abstract 16108: Mutations in the Lamin A/C Gene Play a Major Role in Sudden Arrhythmic Death Syndrome
Introduction: Sudden arrhythmic death syndrome (SADS) is identified in at least 5% of sudden deaths, when no underlying cause of death is revealed. In about half of the SADS cases a comprehensive clinical investigation of first degree relatives identifies a hereditary genetic heart disease. Genetic mutation screening increases the diagnostic yield and thereby the identification of relatives who might benefit prophylactic measures. The LMNA gene encodes the intermediate filaments Lamin A /C, which maintain the structural integrity of the nuclear membrane. Mutations in LMNA are associated with arrhythmias, heart failure and sudden death. Case reports have indicated sudden death as the onset of symptoms in LMNA mutation carriers.
Hypothesis: We assessed the hypothesis, that mutations in LMNA contributes to the causation of SADS.
Methods: In 102 SADS families evaluated from 2000 to 2008 the Lamin A/C gene was Sanger sequenced and analyzed for disease-causing mutations. Applied bioinformatics included the use of dbSNP-database, LOVD database, Human Splicing Finder and the ExPASy Proteomics Server.
Results: Three families (2.9 %) carried a putative disease-causing mutation. One novel (c.1971_1975insC) and two known (c.1680+4A>G and c.1930C>T) mutations were found. None of the mutations were present in 165 healthy controls.The novel mutation introduces a frameshift in exon 12 of the gene, causes skipping of the stop-codon and is believed to elongate the transcript, thereby introducing 38 additional amino acids. The known c.1680+4A>G mutation is predicted to introduce a new splice site causing a frameshift and subsequently the introduction of a premature stop-codon in exon 10, which probably results in haploinsufficiency due to nonsense-mediated mRNA decay. The known c.1930C>T mutation occurs in a well conserved region and causes a charge change at the C-terminal globular tail domain of Lamin A, which could lead to altered interaction with chromatin.
Conclusion: Mutations in the Lamin A/C gene seems to play a major role in the causation of SADS. Consequently it should be assessed in the evaluation of sudden death cases of unknown origin. Furthermore, this study confirms prior case reports, that cardiac laminopathies can have its presentation as SADS at onset.
- © 2010 by American Heart Association, Inc.