A genetic component to familial mitral valve prolapse has been proposed for decades. Despite this, very few genes have been linked to MVP. Here we describe a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages. Detailed clinical evaluation was performed on all the affected family members, which demonstrates a spectrum of MVP morphologies and associated phenotypes. Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which we 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 were obvious pathogenic candidates. Follow-up segregation analysis of all exome-identified variants was done 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. We detected PTPRJ and FLYWCH1 expression 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. Thus, while we cannot exclude a contributory role for PTPRJ and FLYWCH1 in this family, our study underscores the difficulty involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.