Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

Edgar T. Hoorntje, Ilse A. Bollen, Daniela Q. Barge-Schaapveld, Florence H. van Tienen, Gerard J. te Meerman, Joeri A. Jansweijer, Anthonie J. van Essen, Paul G. Volders, Alina A. Constantinescu, Peter C. van den Akker, Karin Y. van Spaendonck-Zwarts, Rogier A. Oldenburg, Carlo L. Marcelis, Jasper J. van der Smagt, Eric A. Hennekam, Aryan Vink, Marianne Bootsma, Emmelien Aten, Arthur A. Wilde, Arthur van den WijngaardJos L. Broers, Jan D. Jongbloed, Jolanda van der Velden, Maarten P. van den Berg, J. Peter van Tintelen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.

Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.

Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

Original languageEnglish
Article number001631
Number of pages36
JournalCirculation : Cardiovascular Genetics
Issue number4
Publication statusPublished - Aug 2017


  • atrial fibrillation
  • atrioventricular block
  • cardiomyopathy, dilated
  • lipodystrophy
  • survival
  • SCN5A


Dive into the research topics of 'Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation'. Together they form a unique fingerprint.

Cite this