{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"dataset_type":["N/A"],"full_dataset_link":["https://ega-archive.org/datasets/EGAD00010000702"],"sample_count":["1"],"description":["EGA dataset EGAD00010000702"],"repository":["EGA"],"title":["Title not provided"],"pubmed_abstract":["Here 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."],"pubmed_title":["Large-scale discovery of novel genetic causes of developmental disorders.","B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability."],"pubmed_authors":["","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 V"],"name_synonyms":["l(3)L6A, TRIO, P1749, M89, CG9208, 1386/06, 2-dichloroethylidene)bis(4-chloro-), Vein, CT29452, UNC-73/Trio., 0368/10, 1, l(3)S138606, l(3)S036810, EBS2, l(3)trio, l(3)rF264, ARHGEF23, DDD, BEST:LD36950, K5, CK5, l(3)10568, l(3)10567, l(3)036810, tgat, l(3)S137203, TDE, l(3)ddd, Vn, CG10491, CG18214, l(3)S095914, Trio, DmelCG18214, 1372/03, ddd, 1'-(2, l(3)S[1386/06], reticular pigment anomaly of flexures, l(3)vn10567, wvn, DTrio, DmelCG10491, l(3)S[1372/3], l(3)6D104, 0959/14, DDD1, Benzene, KRT5A, Dm vn"],"pubmed_title_synonyms":["fg, other disease, scale tissue, human disease, gyltl1b, like-acetylglucosaminyltransferase, scale, gyltl1b-b, acetylglucosaminyltransferase-like protein, MDDGB6, plant peltate hair, peltate hair, mdc1d, familial, disorders, Mbp1, Mbp-1, LARGE, medical condition, LARGE_HUMAN, LARGE1, froggy, Gyltl1a, genetic, BPFD#36, MDC1D, disease, like-glycosyltransferase, enr, diseases, MDDGA6, mKIAA0609, disease or disorder, condition, disorder, diseases and disorders, Homo sapiens disease, inherited genetic, scales, KIAA0609, myd, constitutitional genetic, hereditary, acetylglucosaminyltransferase-like 1A, glycosyltransferase-like protein LARGE1, non-neoplastic."],"description_synonyms":["HSPABP2, l(3)L6A, cg11478, P1749, l(2)k04405, DmelCG10360, Ref(2)P, ALY, 2210017D18Rik, dCHIP, CG5203, ref, ref(2)p, SCAR16, CG30327, 2-dichloroethylidene)bis(4-chloro-), l(2)04405, Vein, CG11478, Ref2P, ref2p, ref(2)Po2, DmelCG5203, CT29452, Ref(2)p, CG6393, p62, THOC4, 1, 2310040B03Rik, EBS2, SDCCAG7, ALY|REF, study, Dmel_CG6393, DmelCG42257, l(3)rF264, DDD, ref(2)Pn., NY-CO-7, dLdb, K5, Ldb, LDB, Chip, ChIP, CK5, l(3)10568, l(3)10567, ALY/REF, CHIP, Chromatin Immunoprecipitation, TDE, l(3)ddd, Vn, CG3924, CG10491, chip, BEF, ddd, 1'-(2, dLDB/Chip, reticular pigment anomaly of flexures, l(3)vn10567, 65K, DmelCG3924, wvn, CG42257, Dmel_CG30327, DmelCG10491, AW046544, DDD1, REF, snp, UBOX1, Benzene, 0610033N24Rik, CG10360, PP1131, KRT5A, Dm vn"],"pubmed_abstract_synonyms":["myosin-light-chain phosphatase activity, PP2A[[C]], PR53, Disorders, PR55, PPP2CB Phosphatase, Floppy, l(3)S026326, Phosphatase, acetylglucosaminyltransferase-like protein, PPP2CA Phosphatase, [X]Other epilepsy (disorder), Epilectic attack, Seizure disorder (disorder), Intellectual Disabilities, Poor school performance, Epilepsy (disorder), PP2A[B], pr53, anon-WO0118547.420, Sialic acid-binding Ig-like lectin 1, Progress Reports, PP2A-Aalpha, Ventriculomegalies, Increased distance between eyes, Agenesis Of, 2-Amino-3-hydroxypropionic acid, Mutations, Palpebral fissures down-slanted, DmelCG7109, B', unspecified, l(3)S031807, PP2A 28D, Summary Report, sry-beta, PP2A[C], Decreased, Dysgeneses, Epileptic attack, Tex271, l(3)01436, myd, Threonin, l(3)S110815, Macrocephaly, Down-slanting palpebral fissures, SER, medium tumor antigen-associated 61 kDa protein, Other forms of epilepsy and recurrent seizures, Retardation, DmelCG6127, Pp2A, Excessive orbital separation, like-acetylglucosaminyltransferase, Progress Report, PP2a, Corpus Callosum Dysgenesis, Dysplastic or absent corpus callosum, l(3)S026226, Epileptic seizure, l(3)S027313, Antimongoloid slant of palpebral fissures, Absent corpus callosum, l(3)S141309, aar, Muscle Tone Poor, Mbp-1, Intellectual, Tone Poor, pp2a, l(3)02414, protein membrane anchor, ser, DmelCG6235, Bd, PR65, Corpus Callosum Absences, l(3)S035505b, Field Reports, Generalized seizure, PP2A, l(3)S048006, Callosal agenesis, Pp2A-28D, l(3)S048013, Retardations, phosphatase, Peripheral hypotonia, PP2A[A], Megacephalies, Hypotonias, Intellectual Development Disorder, l(3)S067915, Cerebral Ventriculomegaly, Too much cerebrospinal fluid in the brain, Epileptic seizures, PROTEIN PHOSPHATASE 2A, Regulatory Subunit, Other forms of epilepsy (disorder), anchoring, CG7901, familial, Downward slanting palpebral fissures, pp2aaalpha, dephosphorylation, l(3)S091905, Development Disorders, PP2-AB, serine/threonine protein phosphatase 2A, Congenital, Epileptic disorder, Protein Phosphatase-2A, 1466/06, PR65A, mKIAA0609, Dysgenesis, DmPp2A-28D, l(3)S029403, EPILEPSY NOS W INTR EPIL, l(3)S033903, Communicating Hydrocephalus, Regulatory Subunit A, Regulatory Subunit B, Large calvaria, CG7913, Intellectual Development Disorders, gamma Isoform, fg, Hydrocephalus, protein phosphatase-2C activity, Wrd, l(3)S042630, Field, pp2A-B', Sheep erythrocyte receptor, Downward slanting of the opening between the eyelids, Down-slanted palpebral fissures, MDC1D, Report, dPP2A A, l(3)S075902b, Epileptic, wrd, enr, A/PR65, l(3)S066813, l(3)S027127, Development Disorder, B56-2, Flaccid, Absence of Corpus Callosum, l(3)S042629, Intellectual Development, B56-1, T10O24_4, l(3)S063110, LD02456, Widely spaced eyes, dPP2A-B56-1, dPP2A-B56-2, Generalized fit, CG5643, Neonatal Hypotonias, Big head, Hypertelorisms, Serine-Threonine-Protein Phosphatase 2A Catalytic Subunit alpha Isoform, Seizure disorder, Other forms of epilepsy, LARGE1, l(3)S132907, Agenesis, Corpus Callosum Agenesis, Cerebral Ventriculomegalies, protein phosphatase activity, l(3)S069206a, l(3)S023141a, B'delta, smooth ER, Down-slanting palpebral fissure, CG17291, Epileptic Seizure, i234, EP - Epilepsy, l(3)S119908, l(3)j11C8, l(3)S046918, Mental Retardation, Siglec-1, PP2A[B'-1], l(3)S088513, dPP2A-Balpha, MDDGB6, sry beta, ligand, Corpus Callosum Absence, Corpus Callosum Hypogenesis, dPP2A-C, ppp2r1a, 5559, BEST:LD02456, Serine Threonine Protein Phosphatase 2A Catalytic Subunit beta Isoform, Epileptic fit, PP2A[B'-2], DPR65, l(3)S029110, Hydrocephalus Ex-Vacuo, Generalised convulsion, TEG-271, Investigative Reports, PP2Ac, constitutitional genetic, ppp2r2c, CG7938, CD169, Epileptic convulsions, Serine Threonine Protein Phosphatase 2A Catalytic Subunit alpha Isoform, PP2Aa, l(3)S076415, epilepsy, l(3)S023938, DPR55, CG 7913, EP3559, Flaccidity, Muscle Tone Atonic, Aqueductal, srya, Idiocy, Megacephaly, sryb, protein phosphatase-2B activity, Muscle Hypotony, Decreased Muscle Tone, Serin, Psychosocial Mental Retardation, DmelCG5643, Down slanting palpebral fissures, EPILEP NEC W/O INTR EPIL, Research Reports, PP2A C, Muscular Flaccidity, PP2A A, Agenesis of the corpus callosum, Hypomyotonia, susceptibility, l(2)02496, PP2AAALPHA, Epilepsy, DmelCG17291, DmelCG7938, Corpus Callosum Hypogeneses, l(2)s5286, Specificity, l(3)S032303, Hypotonia, protein phosphatase 2A, l(3)S075110, Rpw, Epilepsy and recurrent seizures, pp2a-aalpha, tws/aar, EPILEP NOS W/O INTR EPIL, Megalocephalies, l(3)S105605, Substrate Specificities, Protein Phosphatase 2A, Deficiency, CT18858, Mental Deficiency, Muscle Flaccidity, Generalized convulsion, Neonatal Hypotonia, like-glycosyltransferase, Reports, ppp2r2b-a, Hypotony, Generalised seizure, [Myosin light-chain]-phosphatase activity, DEFIC MENTAL, hereditary, sry, Pp2A29B, Severe, protein-membrane adaptor activity, Muscular Hypotonia, Obstructive Hydrocephalus, l(3)S025913, delta Isoform, DmelCG7913, Post Traumatic Hydrocephalus, Mbp1, L-Threonine, PPP2R1A, l(3)S060804, Protein Phosphatase 2, pr65a, std, l(3)S024838, l(3)S025806, srybeta, l(3)S045519, l(3)S043008b, Antimongoloid eye slant, Widened interpupillary distance, Tone Atonic, Tws, Fetal Cerebral Ventriculomegaly, 0318/07, PP2, l(3)S031006, l(3)S053011, Corpus Callosum Malformation, phosphoprotein phosphohydrolase activity, l(3)S080409, Summary Reports, Specificities, sry alpha, l(3)s1801, Hydrocephalus Ex-Vacuos, Disabilities, l(3)S049902, l(3)S067109b, long, TYPE 2A SERINE/THREONINE PROTEIN PHOSPHATASE, Muscle Tone, Dull intelligence, MTS/PP2A, SN, Downward-slanting palpebral fissures, protein phosphatase-1 activity, Aqueductal Stenosis, B56D, genetic, Progress, Floppy Muscle, Increased size of head, Ventriculomegaly, 2-amino-3-hydroxypropanoic acid, v158, Muscles, Fetal, R75353, Hypogenesis, Sa, F20P5.30, Other forms of epilepsy NOS (disorder), myosin-light-chain-phosphate phosphohydrolase activity, Floppy Muscles, Flaccid Muscle Tone, Communicating, ER2-6, l(3)S043029, F20P5_30, l(3)S024834a, tw, PP2a 28D, Generalized seizure (finding), T10O24.4, l(3)S025832, gyltl1b-b, l(3)S022440, CG7109, B/PR55, l(3)S101413b, Pp2A-85F, Epileptic fits, Fetal Cerebral Ventriculomegalies, l(3)S023309, Psychosocial Mental Retardations, l(3)S110008a, Investigative Report, 3-Hydroxyalanine, MDDGA6, Ageneses, Corpus Callosum Ageneses, NOS, Unilateral, seizure disorder, KIAA0609, Large cranium, BcDNA:LD34343, acetylglucosaminyltransferase-like 1A, l(3)S029701a, ptpa, PP2A B', Increased interpupillary distance, gyltl1b, Corpus callosum agenesis, Srybeta, Disability, PPP2CA, PTPA, PPP2CB, mdc1d, CG6235, l(3)S061915, Post-Traumatic, LARGE_HUMAN, CG33297, Big skull, l(3)S066017, l(3)S032708c, CG17957, without mention of intractable epilepsy, l(3)S023206, Epilepsy NOS, Hypogeneses, Patient, l(3)S134601a, Psychosocial intellectual disability, CG6127, l(3)S022361, L Serine, inherited genetic, Sry alpha, l(3)S061805, Mental Retardations, L-Serine, Muscular, Big cranium, Mental, Stenosis, Absence of corpus callosum, MENTAL DEFIC, Deficiencies, with intractable epilepsy, PP2A-29B, Wdb, sryalpha, dPP2A, Nonsyndromal hydrocephalus, l(3)S075515b, Congenital Hydrocephalus, l(3)S111515, CG13383, Obstructive, froggy, Gyltl1a, dPR55, l(3)S048507, Frontal protruberance, Investigative, Skull bossing, mel(3)8, degree (angle)., Epileptic seizure (finding), Cerebral, dB56-2, dB56-1, intellectual disability, BcDNA:GM05554, Downslanting palpebral fissures, PP2A-A, Other forms of epilepsy NOS, B'/PR61, Post-Traumatic Hydrocephalus, PP2A-B, l(3)S022205b, PP2A-C, Sryalpha, myosin light chain kinase phosphatase activity, l(3)S146606, Big calvaria, Low intelligence, LARGE, L Threonine, alpha Isoform, Megalencephalies, Hydrocephaly, BPFD#36, PP2A subunit A isoform R1-alpha, Corpus Callosum, Wide-set eyes, Catalytic Subunit, Clients, Disorder, l(3)S024455, Downward slanted palpebral fissures, EF - Epileptic fit, Generalised fit, Muscle Tone Atonics, Neonatal, l(3)S060203, Muscular Flaccidities, Stenoses, Mts, Mental Deficiencies, Antimongoloid slanted palpebral fissures, l(3)S023013, l(3)S028707, Muscle, l(3)S052810, Client, Psychosocial Mental, Unilateral Hypotonia, Downslanting palpebral fissure, Hydrocephalus Ex Vacuo, protein phosphatase-2A activity, myosin light-chain kinase phosphatase activity, [X]Other epilepsy, beta Isoform, Central hypotonia, EPILEPSY NEC W INTR EPIL, Macrocephalies, Ocular hypertelorism, sry-a, sry-b, Megalocephaly, Corpus Callosum Dysgeneses, phosphoric monoester hydrolase activity, arc degree, Epilepsy NOS (disorder), Large skull, Aqueductal Stenoses, PP2A subunit A isoform PR65-alpha, Intellectual Disability, protein phosphatase 2A-2, Increased distance between eye sockets, Fetal Cerebral, Psychosocial, sry-alpha, Substrate, 2414, 6330556D22Rik, DmelCG17957, Summary, Field Report, glycosyltransferase-like protein LARGE1"],"additional_accession":[]},"is_claimable":false,"name":"DDD_Project_4296_Trio - samples","description":"SNP-chip genotyping data for one proband in the DDD study (Ref : Carvalho AJHG 2015)","dates":{"updated":"2018-11-02 12:01:16"},"accession":"EGAD00010000702","cross_references":{"TAXONOMY":["9606"],"pubmed":["26168268","25533962"],"EGA":["EGAC00001000282","EGAS00001000775"]}}