KEGG   DISEASE: Syndromic X-linked mental retardationHelp
Entry
H00658                      Disease                                

Name
Syndromic X-linked mental retardation
  Subgroup
Renpenning syndrome [DS:H01913]
Christianson syndrome [DS:H01914]
Borjeson-Forssman-Lehmann syndrome [DS:H01915]
MRX Stocco dos Santos type [DS:H01916]
CK syndrome [DS:H01917]
Proud syndrome [DS:H01919]
Partington syndrome [DS:H01920]
MICPCH syndrome [DS:H01921]
MEHMO syndrome [DS:H02195]
X-linked creatine deficiency syndrome [DS:H02196]
Methylmalonic acidemia and homocysteinemia, cblX type [DS:H02222]
MRX Turner type (MRXST)
Siderius type (MRXSSD)
Cabezas type (MRXSC)
Raymond type (MRXSR)
Hedera type (MRXSH)
Claes-Jencen type (MRXSCJ)
Wu type (MRXSW)
Bain type (MRXSB)
Houge type (MRXSHG)
Nascimento type (MRXSN)
FRAXE type
MRX with panhypopituitarism (MRGH)
MRX with cerebellar hypoplasia (MRX60)
Description
X-linked mental retardation (MRX) is an inherited condition that causes failure to develop cognitive abilities because of mutations in several genes on the X chromosome. XLMR is subdivided into syndromic and non-syndromic forms, depending on whether further abnormalities are found or not. Syndromic XLMR is characterized by recognizable dysmorphic features, neurological complications, and/or metabolic abnormalities.
Category
Mental and behavioural disorder
Brite
Human diseases [BR:br08402]
 Other diseases
  Mental and behavioural disorders
   H00658  Syndromic X-linked mental retardation
Human diseases in ICD-11 classification [BR:br08403]
 06 Mental, behavioural or neurodevelopmental disorders
  Neurodevelopmental disorders
   6A00  Disorders of intellectual development
    H00658  Syndromic X-linked mental retardation
BRITE hierarchy
Pathway
hsa04120 Ubiquitin mediated proteolysis   
Gene
(MRXST) HUWE1 [HSA:10075] [KO:K10592]
(MRXSSD) PHF8 [HSA:23133] [KO:K19415]
(MRXSC) CUL4B [HSA:8450] [KO:K10609]
(MRXSR) ZDHHC9 [HSA:51114] [KO:K16675]
(MRXSH) ATP6AP2 [HSA:10159] [KO:K19514]
(MRXSCJ) KDM5C [HSA:8242] [KO:K11446]
(MRXSW) GRIA3 [HSA:2892] [KO:K05199]
(MRXSB) HNRNPH2 [HSA:3188] [KO:K12898]
(MRXSHG) CNKSR2 [HSA:22866] [KO:K17536]
(MRXSN) UBE2A [HSA:7319] [KO:K10573]
(FRAXE) AFF2 [HSA:2334] [KO:K15194]
(MRGH) SOX3 [HSA:6658] [KO:K09267]
(MRX60) OPHN1 [HSA:4983] [KO:K20650]
(MRXS11) RBMX [HSA:27316] [KO:K12885]
(MRXS13) MECP2 [HSA:4204] [KO:K11588]
(MRXS14) UPF3B [HSA:65109] [KO:K14328]
(MRXS32) CLIC2 [HSA:1193] [KO:K05022]
(MRXS33) TAF1 [HSA:6872] [KO:K03125]
(MRXS34) NONO [HSA:4841] [KO:K13214]
Other DBs
ICD-11: 6A00
ICD-10: F78.9
MeSH: D038901
OMIM: 300706 300263 300354 300799 300423 300534 300699 300986 301008 300860 309548 300123 300486 300238 300055 300260 300676 300886 300966 300967
Reference
  Authors
Ropers HH, Hamel BC
  Title
X-linked mental retardation.
  Journal
Nat Rev Genet 6:46-57 (2005)
DOI:10.1038/nrg1501
Reference
  Authors
Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, Chelly J, Sanlaville D, van Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, Hackett A, Marynen P, Turner G, Gecz J
  Title
Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation.
  Journal
Am J Hum Genet 82:432-43 (2008)
DOI:10.1016/j.ajhg.2007.11.002
Reference
  Authors
Qiu J, Shi G, Jia Y, Li J, Wu M, Li J, Dong S, Wong J
  Title
The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation.
  Journal
Cell Res 20:908-18 (2010)
DOI:10.1038/cr.2010.81
Reference
  Authors
Nakagawa T, Xiong Y
  Title
X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression.
  Journal
Mol Cell 43:381-91 (2011)
DOI:10.1016/j.molcel.2011.05.033
Reference
  Authors
Raymond FL, Tarpey PS, Edkins S, Tofts C, O'Meara S, Teague J, Butler A, Stevens C, Barthorpe S, Buck G, Cole J, Dicks E, Gray K, Halliday K, Hills K, Hinton J, Jones D, Menzies A, Perry J, Raine K, Shepherd R, Small A, Varian J, Widaa S, Mallya U, Moon J, Luo Y, Shaw M, Boyle J, Kerr B, Turner G, Quarrell O, Cole T, Easton DF, Wooster R, Bobrow M, Schwartz CE, Gecz J, Stratton MR, Futreal PA
  Title
Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus.
  Journal
Am J Hum Genet 80:982-7 (2007)
DOI:10.1086/513609
Reference
  Authors
Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G, Lubs HA, Engert S, Stevenson RE, Meindl A, Schwartz CE, Nguyen G
  Title
A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor.
  Journal
Hum Mol Genet 14:1019-27 (2005)
DOI:10.1093/hmg/ddi094
Reference
  Authors
Santos-Reboucas CB, Fintelman-Rodrigues N, Jensen LR, Kuss AW, Ribeiro MG, Campos M Jr, Santos JM, Pimentel MM
  Title
A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.
  Journal
Neurosci Lett 498:67-71 (2011)
DOI:10.1016/j.neulet.2011.04.065
Reference
  Authors
Bonnet C, Leheup B, Beri M, Philippe C, Gregoire MJ, Jonveaux P
  Title
Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation.
  Journal
Am J Med Genet A 149A:1280-9 (2009)
DOI:10.1002/ajmg.a.32858
Reference
  Authors
Mircsof D, Langouet M, Rio M, Moutton S, Siquier-Pernet K, Bole-Feysot C, Cagnard N, Nitschke P, Gaspar L, Znidaric M, Alibeu O, Fritz AK, Wolfer DP, Schroter A, Bosshard G, Rudin M, Koester C, Crestani F, Seebeck P, Boddaert N, Prescott K, Hines R, Moss SJ, Fritschy JM, Munnich A, Amiel J, Brown SA, Tyagarajan SK, Colleaux L
  Title
Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects.
  Journal
Nat Neurosci 18:1731-6 (2015)
DOI:10.1038/nn.4169
Reference
  Authors
Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, Gowans G, Autullo LA, Krishnamurthy V, Willing MC, Toler TL, Ben-Zev B, Elpeleg O, Shen Y, Retterer K, Monaghan KG, Chung WK
  Title
Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.
  Journal
Am J Hum Genet 99:728-734 (2016)
DOI:10.1016/j.ajhg.2016.06.028
Reference
  Authors
Moortgat S, Desir J, Benoit V, Boulanger S, Pendeville H, Nassogne MC, Lederer D, Maystadt I
  Title
Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy.
  Journal
Am J Med Genet A 170:2927-2933 (2016)
DOI:10.1002/ajmg.a.37792
Reference
  Authors
Castro NH, dos Santos RC, Nelson R, Becak W, Hane B, Lindsey CJ, Lubs HA, Stevenson RE, Schwartz CE
  Title
Shashi XLMR syndrome: report of a second family.
  Journal
Am J Med Genet A 118A:49-51 (2003)
DOI:10.1002/ajmg.a.10888
Reference
  Authors
Nawara M, Szczaluba K, Poirier K, Chrzanowska K, Pilch J, Bal J, Chelly J, Mazurczak T
  Title
The ARX mutations: a frequent cause of X-linked mental retardation.
  Journal
Am J Med Genet A 140:727-32 (2006)
DOI:10.1002/ajmg.a.31151
Reference
  Authors
Garcia CC, Blair HJ, Seager M, Coulthard A, Tennant S, Buddles M, Curtis A, Goodship JA
  Title
Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy.
  Journal
J Med Genet 41:183-6 (2004)
DOI:10.1136/jmg.2003.013680
Reference
  Authors
Laumonnier F, Ronce N, Hamel BC, Thomas P, Lespinasse J, Raynaud M, Paringaux C, Van Bokhoven H, Kalscheuer V, Fryns JP, Chelly J, Moraine C, Briault S
  Title
Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency.
  Journal
Am J Hum Genet 71:1450-5 (2002)
DOI:10.1086/344661
Reference
  Authors
Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, Smith R, Shoubridge C, Edkins S, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Hills K, Jones D, Mironenko T, Perry J, Varian J, West S, Widaa S, Teague J, Dicks E, Butler A, Menzies A, Richardson D, Jenkinson A, Shepherd R, Raine K, Moon J, Luo Y, Parnau J, Bhat SS, Gardner A, Corbett M, Brooks D, Thomas P, Parkinson-Lawrence E, Porteous ME, Warner JP, Sanderson T, Pearson P, Simensen RJ, Skinner C, Hoganson G, Superneau D, Wooster R, Bobrow M, Turner G, Stevenson RE, Schwartz CE, Futreal PA, Srivastava AK, Stratton MR, Gecz J
  Title
Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.
  Journal
Nat Genet 39:1127-33 (2007)
DOI:10.1038/ng2100
Reference
  Authors
Kumar R, Corbett MA, van Bon BW, Woenig JA, Weir L, Douglas E, Friend KL, Gardner A, Shaw M, Jolly LA, Tan C, Hunter MF, Hackett A, Field M, Palmer EE, Leffler M, Rogers C, Boyle J, Bienek M, Jensen C, Van Buggenhout G, Van Esch H, Hoffmann K, Raynaud M, Zhao H, Reed R, Hu H, Haas SA, Haan E, Kalscheuer VM, Gecz J
  Title
THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.
  Journal
Am J Hum Genet 97:302-10 (2015)
DOI:10.1016/j.ajhg.2015.05.021
Reference
  Authors
Al-Owain M, Kaya N, Al-Zaidan H, Al-Hashmi N, Al-Bakheet A, Al-Muhaizea M, Chedrawi A, Basran RK, Milunsky A
  Title
Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance.
  Journal
Clin Genet 79:363-70 (2011)
DOI:10.1111/j.1399-0004.2010.01462.x
Reference
  Authors
Tonne E, Holdhus R, Stansberg C, Stray-Pedersen A, Petersen K, Brunner HG, Gilissen C, Hoischen A, Prescott T, Steen VM, Fiskerstrand T
  Title
Syndromic X-linked intellectual disability segregating with a missense variant in RLIM.
  Journal
Eur J Hum Genet 23:1652-6 (2015)
DOI:10.1038/ejhg.2015.30
Reference
  Authors
Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, Ropers HH, Tzschach A, Kalscheuer V, Oehl-Jaschkowitz B, Skinner C, Schwartz CE, Gecz J, Van Esch H, Raynaud M, Chelly J, de Brouwer AP, Toniolo D, D'Adamo P
  Title
Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.
  Journal
Am J Hum Genet 86:185-95 (2010)
DOI:10.1016/j.ajhg.2010.01.011
Reference
  Authors
Field M, Tarpey PS, Smith R, Edkins S, O'Meara S, Stevens C, Tofts C, Teague J, Butler A, Dicks E, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Wooster R, Moon J, Luo Y, Hughes H, Shaw M, Friend KL, Corbett M, Turner G, Partington M, Mulley J, Bobrow M, Schwartz C, Stevenson R, Gecz J, Stratton MR, Futreal PA, Raymond FL
  Title
Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly.
  Journal
Am J Hum Genet 81:367-74 (2007)
DOI:10.1086/520677
Reference
  Authors
Mansouri MR, Marklund L, Gustavsson P, Davey E, Carlsson B, Larsson C, White I, Gustavson KH, Dahl N
  Title
Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation.
  Journal
Eur J Hum Genet 13:970-7 (2005)
DOI:10.1038/sj.ejhg.5201445
Reference
  Authors
Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR
  Title
A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.
  Journal
Nat Genet 41:535-43 (2009)
DOI:10.1038/ng.367
Reference
  Authors
de Lange IM, Helbig KL, Weckhuysen S, Moller RS, Velinov M, Dolzhanskaya N, Marsh E, Helbig I, Devinsky O, Tang S, Mefford HC, Myers CT, van Paesschen W, Striano P, van Gassen K, van Kempen M, de Kovel CG, Piard J, Minassian BA, Nezarati MM, Pessoa A, Jacquette A, Maher B, Balestrini S, Sisodiya S, Warde MT, De St Martin A, Chelly J, van 't Slot R, Van Maldergem L, Brilstra EH, Koeleman BP
  Title
De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy.
  Journal
J Med Genet 53:850-858 (2016)
DOI:10.1136/jmedgenet-2016-103909
Reference
  Authors
Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I, Ong LC, Cham B, Tan P, Rozen S, Tan EC
  Title
Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.
  Journal
PLoS One 9:e93409 (2014)
DOI:10.1371/journal.pone.0093409
Reference
  Authors
Willemsen MH, Ba W, Wissink-Lindhout WM, de Brouwer AP, Haas SA, Bienek M, Hu H, Vissers LE, van Bokhoven H, Kalscheuer V, Nadif Kasri N, Kleefstra T
  Title
Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function.
  Journal
J Med Genet 51:487-94 (2014)
DOI:10.1136/jmedgenet-2013-102182
Reference
  Authors
Geetha TS, Michealraj KA, Kabra M, Kaur G, Juyal RC, Thelma BK
  Title
Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
  Journal
Hum Mutat 35:41-4 (2014)
DOI:10.1002/humu.22453
Reference
  Authors
Snijders Blok L, Madsen E, Juusola J, Gilissen C, Baralle D, Reijnders MR, Venselaar H, Helsmoortel C, Cho MT, Hoischen A, Vissers LE, Koemans TS, Wissink-Lindhout W, Eichler EE, Romano C, Van Esch H, Stumpel C, Vreeburg M, Smeets E, Oberndorff K, van Bon BW, Shaw M, Gecz J, Haan E, Bienek M, Jensen C, Loeys BL, Van Dijck A, Innes AM, Racher H, Vermeer S, Di Donato N, Rump A, Tatton-Brown K, Parker MJ, Henderson A, Lynch SA, Fryer A, Ross A, Vasudevan P, Kini U, Newbury-Ecob R, Chandler K, Male A, Dijkstra S, Schieving J, Giltay J, van Gassen KL, Schuurs-Hoeijmakers J, Tan PL, Pediaditakis I, Haas SA, Retterer K, Reed P, Monaghan KG, Haverfield E, Natowicz M, Myers A, Kruer MC, Stein Q, Strauss KA, Brigatti KW, Keating K, Burton BK, Kim KH, Charrow J, Norman J, Foster-Barber A, Kline AD, Kimball A, Zackai E, Harr M, Fox J, McLaughlin J, Lindstrom K, Haude KM, van Roozendaal K, Brunner H, Chung WK, Kooy RF, Pfundt R, Kalscheuer V, Mehta SG, Katsanis N, Kleefstra T
  Title
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.
  Journal
Am J Hum Genet 97:343-52 (2015)
DOI:10.1016/j.ajhg.2015.07.004
Reference
  Authors
Damiano JA, Burgess R, Kivity S, Lerman-Sagie T, Afawi Z, Scheffer IE, Berkovic SF, Hildebrand MS
  Title
Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum.
  Journal
Epilepsia 58:e40-e43 (2017)
DOI:10.1111/epi.13666
Reference
  Authors
Nascimento RM, Otto PA, de Brouwer AP, Vianna-Morgante AM
  Title
UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome.
  Journal
Am J Hum Genet 79:549-55 (2006)
DOI:10.1086/507047
Reference
  Authors
Takano K, Liu D, Tarpey P, Gallant E, Lam A, Witham S, Alexov E, Chaubey A, Stevenson RE, Schwartz CE, Board PG, Dulhunty AF
  Title
An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.
  Journal
Hum Mol Genet 21:4497-507 (2012)
DOI:10.1093/hmg/dds292
Reference
  Authors
O'Rawe JA, Wu Y, Dorfel MJ, Rope AF, Au PY, Parboosingh JS, Moon S, Kousi M, Kosma K, Smith CS, Tzetis M, Schuette JL, Hufnagel RB, Prada CE, Martinez F, Orellana C, Crain J, Caro-Llopis A, Oltra S, Monfort S, Jimenez-Barron LT, Swensen J, Ellingwood S, Smith R, Fang H, Ospina S, Stegmann S, Den Hollander N, Mittelman D, Highnam G, Robison R, Yang E, Faivre L, Roubertie A, Riviere JB, Monaghan KG, Wang K, Davis EE, Katsanis N, Kalscheuer VM, Wang EH, Metcalfe K, Kleefstra T, Innes AM, Kitsiou-Tzeli S, Rosello M, Keegan CE, Lyon GJ
  Title
TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.
  Journal
Am J Hum Genet 97:922-32 (2015)
DOI:10.1016/j.ajhg.2015.11.005
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