BACKGROUND: hypertrophic cardiomyopathy (HCM) is a major cause of sudden death 
in young athletes and one of the most common inherited cardiovascular diseases, 
affecting 1 in 500 individuals. Often viewed as a disease of the cardiac 
sarcomere, mutations in genes encoding myofilament proteins are associated with 
disease pathogenesis. Despite a clinically available genetic test, a significant 
portion of HCM patients remain genetically unexplained. We sought to determine 
the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large 
cohort of HCM cases as a potential cause of mutation-negative HCM.
METHODS: comprehensive genetic interrogation of the promoter and coding region 
of PLN was conducted using polymerase chain reaction, denaturing 
high-performance liquid chromatography, and direct DNA sequencing.
RESULTS: one L39X nonsense mutation was identified in 1 of 1,064 HCM proband 
cases with a family history of HCM, previously found to be negative for the 
current HCM genetic test panel. This mutation cosegregated with incidence of HCM 
in a multigenerational family. Compared with similar studies, we identified an 
overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of 
current HCM genetic test panels. We did not observe any PLN coding sequence 
genetic variation in 600 reference alleles.
CONCLUSIONS: overall, mutations in PLN are rare in frequency, yet the small size 
of the genetic locus may make it amenable to inclusion on HCM gene test panels, 
especially because the frequency of background genetic variation among otherwise 
healthy subjects appears negligible. The exact role of mutations in PLN and 
other calcium-handling proteins in the development of HCM warrants further 
investigation.