Abstract 17982: A lamin A/C Synonymous Mutation Creates a Novel Splice Site and Causes Progressive Atrioventricular Conduction Defect
Background: Mutations in the lamin A/C, encoded by LMNA, produce diverse genetic disorders, collectively termed laminopathies including disease of cardiac and skeletal muscles, peripheral neuropathy, lipodystrophy and premature aging syndromes. Cardiac phenotypes associated with LMNA mutations include progressive cardiac conduction defects and dilated cardiomyopathy (DCM), and this has been attributed predominantly to missense variants and less commonly to truncating variants. Synonymous sequence variants are usually considered benign and have not been investigated in cardiac laminopathies. Here we report the identification of A LMNA synonymous mutation that mimics a splice donor consensus sequence and causes a 15 amino acid deletion in the exon 4.
Methods and Results: We conducted a linkage analysis by genome-wide SNP genotyping method and found one region with LOD score > 4 on chr1q21.3-q23.3, which includes LMNA. Exome sequencing was performed in 4 affected subjects. 3 unique variants that were shared by the affected Subjects were identified in the linkage region. One variant, a synonymous change in the LMNA gene, was selected for further analysis, since LMNA is a strong candidate gene for the family’s phenotype and the variant was predicted to introduce a new potential splice donor site. Sanger sequencing samples from the extended pedigree confirmed that the synonymous LMNA variant was present in all affected subjects and absent from unaffected subjects. Evaluation of myocardial tissue from one affected family member using RT-PCR showed the expected band of 240 bp size and an additional smaller band of 195 bp size, suggestive a potential effect of the variant on RNA splicing. Sanger sequencing of the smaller band revealed a 45-bp in-frame deletion in the tail of the exon4, indicating that this variant activates a cryptic splice donor site.
Conclusion: Here we report a novel synonymous LMNA variant, c.768G>A, in a family with DCM and conduction-system disease, this variant appears to alter RNA splicing by activating a cryptic splice donor site. These findings expand the spectrum of LMNA mutations associated with cardiac laminopathies and highlight the potential pathogenicity of synonymous sequence variants.
Author Disclosures: K. Ito: None. B. McDonough: None. J.M. Gorham: None. S.R. DeParma: None. E.E. Adler: None. S.M. Mohiuddin: None. D. Fatkin: None. J.G. Seidman: None. C.E. Seidman: None.
- © 2014 by American Heart Association, Inc.