Genetic variants in the gene POPDC2 cause heart rhythm problems and muscle thickening
Today, only just over 40% of all patients diagnosed with hypertrophic cardiomyopathy, HCM, have a mutation that can be detected with a gene test. This leaves families and doctors at a loss when it comes to confirming the diagnosis in the remaining 60% of HCM cases, and above all makes it impossible to in such families explore which relatives have the mutated gene for HCM – and which ones do not.
Here comes a study that finds one additional, but rare, gene change behind HCM.
This recent international study discovered that changes in both copies of a gene called POPDC2 can cause this inherited heart condition. The condition can lead to problems with the heart’s electrical system (which controls the heartbeat) and can thus result in hypertrophic cardiomyopathy, where the heart muscle becomes abnormally thick.
The researchers studied eight people from four unrelated families, all of whom had different combinations of heart rhythm disturbances—like sinus node dysfunction (slow or irregular heart rhythm), AV block (a delay or interruption in the electrical signal between the heart’s chambers), and hypertrophic cardiomyopathy. All of these individuals had two faulty copies of the POPDC2 gene—one from each parent. This means the condition follows a recessive inheritance pattern.
The POPDC2 gene is especially active in the heart’s conduction system, the specialized tissue that sends electrical signals to make the heart beat. This might explain why mutations in this gene cause electrical heart problems. Importantly, in a large population of more than 1 million individuals, the study showed that people with only one faulty copy of the gene (carriers) appear to be healthy.
These discoveries help doctors better diagnose unexplained early heart rhythm problems and hypertrophic cardiomyopathy and could inform genetic testing panels used in cardiology clinics across the world. It is important to note that this gene is inherited in a different way from previously known “HCM genes” – this new rare POPDC2 gene is recessive meaning that only when both parents have this trait can it be transmitted to their children.
Nicastro M, Vermeer AMC, Postema PG, Tadros R, Bowling FZ, Aegisdottir HM, Tragante V, Mach L, Postma AV, Lodder EM, van Duijvenboden K, Zwart R, Beekman L, Wu L, Jurgens SJ, van der Zwaag PA, Alders M, Allouba M, Aguib Y, Santome JL, de Una D, Monserrat L, Miranda AMA, Kanemaru K, Cranley J, van Zeggeren IE, Aronica EMA, Ripolone M, Zanotti S, Sveinbjornsson G, Ivarsdottir EV, Hólm H, Guðbjartsson DF, Skúladóttir ÁT, Stefánsson K, Nadauld L, Knowlton KU, Ostrowski SR, Sørensen E, Vesterager Pedersen OB, Ghouse J, Rand SA, Bundgaard H, Ullum H, Erikstrup C, Aagaard B, Bruun MT, Christiansen M, Jensen HK, Carere DA, Cummings CT, Fishler K, Tørring PM, Brusgaard K, Juul TM, Saaby L, Winkel BG, Mogensen J, Fortunato F, Comi GP, Ronchi D, van Tintelen JP, Noseda M, Airola MV, Christiaans I, Wilde AAM, Wilders R, Clur SA, Verkerk AO, Bezzina CR, Lahrouchi N. Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy. Am J Hum Genet. 2025 Jul 3;112(7):1681-1698. doi: 10.1016/j.ajhg.2025.04.016. Epub 2025 May 22. PMID: 40409267; PMCID: PMC12256823.
Prepared by Najim Lahrouchi and Jerker Liljestrand