EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD000010101360EGA dataset EGAD00001010136EGAHere we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.Large-scale discovery of novel genetic causes of developmental disorders.B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.Houge Gunnar G, Haesen Dorien D, Vissers Lisenka E L M LE, Mehta Sarju S, Parker Michael J MJ, Wright Michael M, Vogt Julie J, McKee Shane S, Tolmie John L JL, Cordeiro Nuno N, Kleefstra Tjitske T, Willemsen Marjolein H MH, Reijnders Margot R F MR, Berland Siren S, Hayman Eli E, Lahat Eli E, Brilstra Eva H EH, van Gassen Koen L I KL, Zonneveld-Huijssoon Evelien E, de Bie Charlotte I CI, Hoischen Alexander A, Eichler Evan E EE, Holdhus Rita R, Steen Vidar M VM, Døskeland Stein Ove SO, Hurles Matthew E ME, FitzPatrick David R DR, Janssens Veerle VfalseEGAS00001000775-sc-2023-03-15T11:15:06Z - samplesDDD resource files (e.g. link between sample and individual ids)2023-05-25 13:41:21EGAD0000101013696062616826825533962EGAC00001000282EGAS00001000775