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You are here: Contents > 2017 > Volume 26 Number 5 September 2017 > MITRAL VALVE DISEASE > Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family

Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family

Gloria T. Haskell1,9, Brian C. Jensen2,3,4, Cecile Skrzynia1, Thelsa Pulikkotil3,5, Christian R. Tilley1, Yurong Lu1, Daniel S. Marchuk1, Leigh Ann Samsa4,6, Kirk C. Wilhelmsen1,7, Ethan Lange1, Cam Patterson8, James P. Evans1, Jonathan S. Berg1

1Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
2Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA
3Division of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, NC, USA
4University of North Carolina McAllister Heart Institute, University of North Carolina at Chapel Hill, NC, USA
5Kaiser Permanente, Atlanta, GA, USA
6Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC, USA
7Renaissance Computing Institute, Chapel Hill, NC, USA
8Departments of Medicine and Cardiology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, USA
9Electronic correspondence: gloria.haskell@duke.edu

Background and aim of the study: A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages.

Methods: A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes.

Results: Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the

 

family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when ‘affected’ was broadly defined.  

Conclusion: While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.

The Journal of Heart Valve Disease 2017;26:569-580


Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family

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