von Christoph Jüschke ; Kira Linsel ; Marta Owczarek-Lipska ; Nicola Brandt ; Sarah Zunken ; Janine Altmüller ; Markus N. Preising ; Dennis Kastrati ; Holger Thiele ; Mervyn G. Thomas ; Peter Nürnberg ; Birgit Lorenz ; Ulrich Kellner ; Anja U. Bräuer ; Christoph Korenke ; Irene Gottlob ; John Neidhardt
von Sophie Hordijk ; Stijn A. Groten ; Petra E. Bürgisser ; Sebastiaan N. J. Laan ; Christoph Korenke ; Tomáš Honzík ; Diane Beysen ; Frank W. G. Leebeek ; Paul A. Skehel ; Maartje van den Biggelaar ; Tom Carter ; Ruben Bierings
von Iris Verbinnen ; Sofia Douzgou Houge ; Tzung-Chien Hsieh ; Hellen Lesmann ; Aron Kirchhoff ; David Geneviève ; Elise Brimble ; Lisa Lenaerts ; Dorien Haesen ; Rebecca J. Levy ; Julien Thevenon ; Laurence Faivre ; Elysa Marco ; Jessica X. Chong ; Mike Bamshad ; Karynne Patterson ; Ghayda M. Mirzaa ; Kimberly Foss ; William Dobyns ; Susan M. White ; Lynn Pais ; Emily O’Heir ; Raphaela Itzikowitz ; Kirsten A. Donald ; Celia Van der Merwe ; Alessandro Mussa ; Raffaela Cervini ; Elisa Giorgio ; Tony Roscioli ; Kerith-Rae Dias ; Carey-Anne Evans ; Natasha J. Brown ; Anna Ruiz ; Juan Pablo Trujillo Quintero ; Rachel Rabin ; John Pappas ; Hai Yuan ; Katherine Lachlan ; Simon Thomas ; Anita Devlin ; Michael Wright ; Richard Martin ; Joanna Karwowska ; Renata Posmyk ; Nicolas Chatron ; Zornitza Stark ; Oliver Heath ; Martin Delatycki ; Rebecca Buchert ; Christoph Korenke ; Keri Ramsey ; Vinodh Narayanan ; Dorothy K. Grange ; Judith L. Weisenberg ; Tobias B. Haack ; Stephanie Karch ; Patricia Kipkemoi ; Moses Mangi ; Karen G. C. B. Bindels de Heus ; Marie-Claire Y. de Wit ; Tahsin Stefan Barakat ; Derek Lim ; Géraldine Van Winckel ; Rebecca C. Spillmann ; Vandana Shashi ; Maureen Jacob ; Antonia M. Stehr ; Peter Krawitz ; Gunnar Douzgos Houge ; Veerle Janssens
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 resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 112(2025), 3 vom: März, Seite 554-571
