biostudies-literatureStellacci EItalian Ministry of HealthMinistero della SaluteCommon FundNHGRI NIH HHSNINDS NIH HHSEuropean Joint Programme on Rare Diseases, EJP-RD: NSEuroNetNIH Common FundAssociazione Italiana per la Ricerca sul Cancro, AIRCe63627https://www.ebi.ac.uk/biostudies/studies/S-EPMC11223960biostudies-literatureUnknown194(8)Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotoAmerican journal of medical genetics. Part AImmunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.PMC11223960U01HG010218IG 28768U01 HG010218U01 NS134358Venanzi SDasari SDouglas JCole FSUndiagnosed Diseases NetworkStellacci EEmrick LTSkelton TWener MCallaway KNovacic DMalicdan MCVRajagopalan RTaylor HWorley KSutton SCuddapah VCarter JNButte MJJobanputra VWalker MStoler JMEzell KJean-Marie OKarasozen YLeppig KABonner DGropman ASeto ECoakley TRPallais JCFieg ELBellen HJAcosta MTHurst APosey JELanza IRRebelo ASilverman EKSirugo GMiller DJarvik GPVogel TPAdams DRTartaglia MKrakow DByers PMartin MGMartinelli SShelkowitz EBale JFisher PGFogel BLMaghiro AMahoney RLanpher BCScott DASmith CAPhillips JAWhitlock JPetcharet LSweetser DAPannone LAlvey JTran AAMacnamara EFCobban LARaper ADavis JKorf BTarakad AMarth GCogan JDMoslehi DAllenspach EMulvihill LBivona STabor HKWenger TGonzalez JMBejerano GCraigen WJMight MWangler MFPak SZuchner SBayrak-Toydemir PHisama FMMartin BAHayes NLongo NKetkar SRosenfeld JAMao RSkraban CLiu PSullivan KWambach JAlvarez RLLalani SRDorrani NParker NHBlue EOrengo JPThorson WWheeler MTHing AHorike-Pyne MMartinez-Agosto JABennett JCarvalho GKilich GBamshad MZhang ZTekin MEng CMD'Souza PHom JKravets EPeart LHanchard NNelson SFHalley MCSmith KSSheppeard SSybert VDelgado MLatchman KIntrone WBohnsack JNitsuh DTifft CJBaldridge DLewis RADarr KHolm IASolomon BSolnica-Krezel LClark GDRodan LHAfzali BCorona RIByrd WEKohane ISBaldwin EBeck AMoretti PPotocki LCrouse ABGlass IMikati MWegner DRives LCoggins MAndrews AKiley DShashi VBehrens EBotto LAshley EABacino CAChanprasert SBarbouth DBriere LCQuinlan ARuzhnikov MWood HBeggs AHMarwaha SNakano-Okuno MHuang YHamid RFu JMitchell BReuter CMDai HSpillmann RCGoddard PCSisco KGlanton EVanderver ABalasubramanyam ABurrage LCMorimoto MShin JSchoch KMarom RSunyaev SRUngar RAToro CPace LLee BHCassini TChao HTEsteves CHuang AOglesbee DVelinder MMcConkie-Rosell AStergachis AMaduro VVGanetzky RYamamoto SViskochil DCarey JStevenson DSampson JBBademci GSwerdzewski BNPHigh FBernstein JABerry GTTan QRader DJBican ABurke EARodriguez MKobren SNLeBlanc KLam CRossignol FWalley NMVairo FPHassey KWard PAEarl DMacRae CAHubshman MWRosenthal EChinn IKlee EDoherty DMirzaa GCorner BAllworth AMaas RLGahl WALoscalzo JMulvihill JJSchedl TJayadev SRao DASchimmenti LDipple KKanca OMcMinn AAl-Beshri ANeumann SWolfe LAKorrick SRaskind WDell'Angelica ECBorja NWesterfield MDouine EDSabaii MWahl CEfalseImmunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomoto2024-01-01T00:00:00Z2024 Aug2026-03-18T13:25:34.303Z2025-08-18T09:53:51.302ZS-EPMC112239603861316810.1002/ajmg.a.63627