Recurrent somatic mutations of in isolated cardiac myxoma.

Background: Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in . Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated.

Methods: We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens.

Results: 87.5% (7/8) of ICM harbored mutations in . Three of the 8 ICM harbored biallelic somatic mutations of , including c.607_610del:p.Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A>G (pathogenic) and c.178-1 G>C (pathogenic) + c. 550+1 G>C (pathogenic). Four of 8 tumors harbored monoallelic mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating mutations.

Conclusion: Our findings suggest that loss-of-function mutations of may play a vital role in the formation of isolated cardiac myxomas.