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About 80% of the index cases have germline mutations in <jats:italic>PRKAR1A<\/jats:italic> encoding the RI\u03b1 regulatory subunit of cAMP-dependent protein kinase A (PKA). However, the role of <jats:italic>PRKAR1A<\/jats:italic> gene mutations in the pathogenesis of non-CNC-associated sporadic cardiac myxoma is less well established. Here, we investigated the presence of <jats:italic>PRKAR1A<\/jats:italic> 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 <jats:italic>PRKAR1A<\/jats:italic> 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 <jats:italic>PRKAR1A<\/jats:italic> genetic alterations involved missense mutations, often located in important functional domains of the regulatory subunit RI\u03b1. Notably, 64% (<jats:italic>n<\/jats:italic>\u2009=\u20099\/14) of the cases harbored more than one <jats:italic>PRKAR1A<\/jats:italic> gene variant, suggesting compound heterozygous mutations either in <jats:italic>cis<\/jats:italic> or <jats:italic>trans<\/jats:italic>. In conclusion, <jats:italic>PRKAR1A<\/jats:italic> gene mutations associated with loss of RI\u03b1 function leading to increased PKA activity were observed in\u2009~\u200960% of sporadic cardiac myxomas, strongly supporting an essential role for PKA in mediating formation of cardiac myxoma.<\/jats:p>","DOI":"10.1007\/s00428-025-04049-x","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T19:31:07Z","timestamp":1739907067000},"page":"511-519","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Detection of PRKAR1A gene mutations in sporadic cardiac myxomas: a study of 24 cases"],"prefix":"10.1007","volume":"486","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5159-1697","authenticated-orcid":false,"given":"Elise","family":"Bekers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4289-2807","authenticated-orcid":false,"given":"Diede A. 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