biostudies-literatureVerbinnen IKU Leuven Research CouncilNINDS NIH HHSResearch Foundation Flanders554-571https://www.ebi.ac.uk/biostudies/studies/S-EPMC11947181biostudies-literatureUnknown112(3)Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resembAmerican journal of human geneticsPathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.PMC11947181U01 NS134350U01 NS134355Thevenon JSpillmann RCVan Winckel Gde Wit MYHsieh TCPatterson KUndiagnosed Diseases NetworkLenaerts LHaack TBDouzgos Houge GVerbinnen IWright MKipkemoi PDouzgou Houge SCervini RStark ZBuchert RKarwowska JJacob MRoscioli TWhite SMGrange DKMartin RHeath OYuan HDelatycki MFoss KBindels de Heus KGCBKirchhoff AVan der Merwe CDevlin AKorenke GCBrown NJPappas JJanssens VDonald KADobyns WFaivre LLachlan KMirzaa GMChatron NShashi VMangi MBarakat TSO'Heir ERabin RWeisenberg JLLevy RJChong JXThomas SPosmyk RBrimble EKrawitz PGiorgio EStehr AMNarayanan VGenevieve DLesmann HPais LMussa ADias KREvans CABamshad MItzikowitz RMarco ETrujillo Quintero JPLim DRamsey KHaesen DRuiz AKarch SfalsePathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemb2025-01-01T00:00:00Z2025 Mar2026-06-01T13:59:41.742Z2026-04-08T13:11:28.149ZS-EPMC119471813997834210.1016/j.ajhg.2025.01.021