biostudies-literatureDonkervoort SNational Institute of Neurological Disorders and StrokeSilicon Valley Community FoundationNHGRI NIH HHSCommon FundNINDS NIH HHSNational Human Genome Research Institute629-640https://www.ebi.ac.uk/biostudies/studies/S-EPMC10963296biostudies-literatureUnknown11(3)<h4>Objective</h4>ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.<h4>Methods</h4>We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.<h4>Results</h4>We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype ofAnnals of clinical and translational neurologyRecurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.PMC10963296U01HG010218U01 HG010218R01 HG009141U01 NS134356UM1 HG008900UM1HG008900K22 NS104135Dasari SCole FSUndiagnosed Diseases NetworkEmrick LTBonnemann CGCrunk AWener MNovacic DMalicdan MCVTaylor HDyment DAWorley KSutton SCunningham MButte MJJobanputra VWalker MStoler JMJean-Marie OBonner DGropman AHartley TLoo SKSeto ECoakley TRPallais JCFieg ELPapp JCBellen HJAcosta MTPosey JELanza IRMohassel PSilverman EKMiller DDayal JGJarvik GPVogel TPAdams DRKrakow DByers PMartin MGShelkowitz EBale JFisher PGFogel BLMaghiro AMcWalter KMahoney RRenteria GSinsheimer JSLanpher BCIzumi KScott DAMcCray ATPhillips JAWhitlock JPetcharet LSweetser DAAlvey JTran AAMacnamara EFCobban LARaper ADavis JTarakad AMarth GCogan JDWang LKBivona STabor HKSharma PWenger TPusey Swerdzewski BNMozaffar TBejerano GBonner DEJarvik JCraigen WJMight MWangler MFCohen JSPak SZuchner SBayrak-Toydemir PHisama FMMartin BAHayes NLongo NKetkar SRosenfeld JAMao RLiu PSullivan KMamounas LAAmelia LMTWambach JAlvarez RLLalani SRDorrani NParker NHBlue EAustin-Tse COrengo JPHurth KThorson WWheeler MTHing AHorike-Pyne MMartinez-Agosto JAO'Donnell-Luria ABennett JKilich GBamshad MCorona RZhang ZTekin MEng CMD'Souza PHom JKravets EHanchard NNelson SFHalley MCSmith KSSaporta MASheppeard SSybert VDelgado MIntrone WKrasnewich DMBohnsack JUrv TKTifft CJWan JBaldridge DLewis RAHolm IASolomon BSolnica-Krezel LClark GDFoley ARRodan LHAfzali BByrd WEKohane ISNieves-Rodriguez SBeck AMoretti PPotocki LCrouse ABGlass IMikati MDonkervoort SWegner DDoss ALHutchison SRives LCoggins MAndrews AKiley DKohler JNShashi VBehrens EO'Leary MBotto LAshley EABacino CAChanprasert SEckstein DJBarbouth DBriere LCQuinlan ARuzhnikov MBeggs AHMarwaha SNakano-Okuno MHuang YHamid RFu JReuter CMDai HSpillmann RCGoddard PCSisco KVanderver ABalasubramanyam ABurrage LCMorimoto MShin JBrown GSchoch KMarom RUngar RAManolio TAToro CPace LLee BHCassini TChao HTHuang AOglesbee DMammen ALBrull AVelinder MMcConkie-Rosell AStergachis AMorava EMaduro VVYamamoto SViskochil DCarey JSampson JBBademci GFalk MHigh FBernstein JAAcquaye NBerry GTBican ABurke EAKobren SNLeBlanc KLam CRossignol FWalley NMRobertson AKHassey KWard PAEarl DMcGee EMacRae CAHubshman MWKaitryn ERosenthal EChinn IDoherty DMirzaa GAllworth AWarman-Chardon JMaas RLColley HAGahl WALoscalzo JMulvihill JJSchedl TJayadev SRao DADipple KWolfe LAKorrick SRaskind WDell'Angelica ECPajusalu SGodfrey RATan QKWesterfield MDouine EDSabaii MWahl CEfalseRecurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.<h4>Objective</h4>ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.<h4>Methods</h4>We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.<h4>Results</h4>We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of2024-01-01T00:00:00Z2024 Mar2026-07-15T14:52:53.242Z2025-04-06T19:02:48.322ZS-EPMC109632963831179910.1002/acn3.51983