Abstract
The benign neoplasm cardiac myxoma represents one of the hallmarks of Carney complex (CNC), a familial multiple neoplasia syndrome. About 80% of the index cases have germline mutations in PRKAR1A encoding the RIα regulatory subunit of cAMP-dependent protein kinase A (PKA). However, the role of PRKAR1A gene mutations in the pathogenesis of non-CNC-associated sporadic cardiac myxoma is less well established. Here, we investigated the presence of PRKAR1A gene variants in a cohort of 24 sporadic cardiac myxomas using targeted next-generation sequencing. Our study shows that 14 out of 24 cases (58%) harbor PRKAR1A gene mutations, represented mostly by frameshift, nonsense, and splice site mutations (together 84%), leading to a premature stop codon predicted to be degraded via non-sense mediated mRNA decay. The other 16% of PRKAR1A genetic alterations involved missense mutations, often located in important functional domains of the regulatory subunit RIα. Notably, 64% (n = 9/14) of the cases harbored more than one PRKAR1A gene variant, suggesting compound heterozygous mutations either in cis or trans. In conclusion, PRKAR1A gene mutations associated with loss of RIα function leading to increased PKA activity were observed in ~ 60% of sporadic cardiac myxomas, strongly supporting an essential role for PKA in mediating formation of cardiac myxoma.