RESUMEN
BACKGROUND: 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. CONCLUSIONS: 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.
