Details of Disease

General Information of Disease (ID: DISJWRZZ)

• Disease Name: Autosomal recessive non-syndromic intellectual disability
• Synonyms: autosomal recessive non-syndromic intellectual disability; non-syndromic intellectual disability, autosomal recessive; mental retardation, autosomal recessive; autosomal recessive intellectual disability; autosomal recessive mental retardation; NS-ARID; AR-NSID; intellectual disability, autosomal recessive; autosomal recessive non-syndromic mental retardation
• Definition: Autosomal recessive form of non-syndromic intellectual disability.|Editor note: misclassified in Orphanet: https://github.com/monarch-initiative/monarch-disease-ontology/issues/407
• Disease Hierarchy:
  DISCPWH9: Autosomal recessive disease
  DISD715V: Hereditary neurological disease
  DIS6ZIDS: Disorder of carbohydrate transmembrane transport and absorption
  DISTFIZ6: Non-syndromic intellectual disability
  DISJWRZZ: Autosomal recessive non-syndromic intellectual disability
• Disease Identifiers:
  MONDO ID: MONDO_0019502
  UMLS CUI: C5680181
  MedGen ID: 1826073
  Orphanet ID: 88616

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 44 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
TUSC3	OTE1V2P2	Supportive	Autosomal recessive	[1]
UBE4A	OTO4BYWL	Supportive	Autosomal recessive	[2]
UFSP2	OTTO00PC	Supportive	Autosomal recessive	[3]
WASHC4	OTYIHCXJ	Supportive	Autosomal recessive	[4]
ZC3H14	OTX6U72I	Supportive	Autosomal recessive	[5]
AIMP1	OTTA5C3U	Supportive	Autosomal recessive	[16]
ALKBH8	OTXN70DV	Supportive	Autosomal recessive	[17]
B3GALNT2	OTOF6O2B	Supportive	Autosomal recessive	[18]
CC2D1A	OTVPU04K	Supportive	Autosomal recessive	[19]
CLIP1	OTTGAEJE	Supportive	Autosomal recessive	[20]
CRADD	OT02TZ4S	Supportive	Autosomal recessive	[21]
CRBN	OTXH9MDC	Supportive	Autosomal recessive	[6]
DCPS	OT1FZVC9	Supportive	Autosomal recessive	[7]
EDC3	OTYS7O69	Supportive	Autosomal recessive	[7]
EZR	OTHBPF1Z	Supportive	Autosomal recessive	[8]
FBXO31	OTF96IC2	Supportive	Autosomal recessive	[22]
FMN2	OTUY7BSV	Supportive	Autosomal recessive	[23]
FRRS1L	OT24ABVC	Supportive	Autosomal recessive	[24]
GRIK2	OTQ41U3D	Supportive	Autosomal recessive	[9]
HNMT	OT9F303M	Supportive	Autosomal recessive	[15]
IQSEC1	OTK1PBFD	Supportive	Autosomal recessive	[25]
KDM5B	OT5DL94T	Supportive	Autosomal recessive	[10]
LINS1	OT1USO08	Supportive	Autosomal recessive	[26]
LMAN2L	OTJ9FAWS	Supportive	Autosomal recessive	[27]
MAN1B1	OTI780UB	Supportive	Autosomal recessive	[28]
MBOAT7	OTHRCBLK	Supportive	Autosomal recessive	[29]
MED23	OTKZQT0R	Supportive	Autosomal recessive	[30]
MED25	OTDBY87B	Supportive	Autosomal recessive	[31]
METTL23	OTO7O557	Supportive	Autosomal recessive	[32]
NCDN	OT5CE7LO	Supportive	Autosomal recessive	[33]
NDST1	OT9E10W2	Supportive	Autosomal recessive	[34]
NSUN2	OTZCNM33	Supportive	Autosomal recessive	[35]
PGAP1	OT1WQ55V	Supportive	Autosomal recessive	[36]
PIGC	OTDFW5KH	Supportive	Autosomal recessive	[37]
PRSS12	OT1MYL3L	Supportive	Autosomal recessive	[11]
RSRC1	OTFCJ4S0	Supportive	Autosomal recessive	[38]
SARS1	OTFKXQ1O	Supportive	Autosomal recessive	[39]
SLC12A2	OT3ZJ3LH	Supportive	Autosomal recessive	[13]
SLC45A1	OTS4J679	Supportive	Autosomal recessive	[14]
ST3GAL3	OTOORKUE	Supportive	Autosomal recessive	[40]
TECR	OT2NT4MV	Supportive	Autosomal recessive	[41]
TNIK	OTDZBJ4K	Supportive	Autosomal recessive	[12]
TRAPPC9	OTF0CVMC	Supportive	Autosomal recessive	[42]
TTC5	OTWW9ME0	Supportive	Autosomal recessive	[43]

This Disease Is Related to 7 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CRBN	TTDKGTC	Supportive	Autosomal recessive	[6]
DCPS	TTLSW9V	Supportive	Autosomal recessive	[7]
EZR	TTE47YC	Supportive	Autosomal recessive	[8]
GRIK2	TT0K5RG	Supportive	Autosomal recessive	[9]
KDM5B	TTCLI75	Supportive	Autosomal recessive	[10]
PRSS12	TT2JYUE	Supportive	Autosomal recessive	[11]
TNIK	TTPB1W3	Supportive	Autosomal recessive	[12]

This Disease Is Related to 3 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC12A2	DTHKL3Q	Supportive	Autosomal recessive	[13]
SLC45A1	DTMSNOU	Supportive	Autosomal recessive	[14]
TUSC3	DTF6R81	Supportive	Autosomal recessive	[1]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
HNMT	DE3PZ0I	Supportive	Autosomal recessive	[15]

References

• [1] A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family. Am J Med Genet A. 2011 Aug;155A(8):1976-80. doi: 10.1002/ajmg.a.34077. Epub 2011 Jul 7.
• [2] Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genet Med. 2021 Apr;23(4):661-668. doi: 10.1038/s41436-020-01047-z. Epub 2021 Jan 8.
• [3] A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy. Genet Med. 2021 May;23(5):900-908. doi: 10.1038/s41436-020-01071-z. Epub 2021 Jan 20.
• [4] Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP. Hum Mol Genet. 2011 Jul 1;20(13):2585-90. doi: 10.1093/hmg/ddr158. Epub 2011 Apr 15.
• [5] Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans. Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12390-5. doi: 10.1073/pnas.1107103108. Epub 2011 Jul 6.
• [6] A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology. 2004 Nov 23;63(10):1927-31. doi: 10.1212/01.wnl.0000146196.01316.a2.
• [7] Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Hum Mol Genet. 2015 Jun 1;24(11):3172-80. doi: 10.1093/hmg/ddv069. Epub 2015 Feb 20.
• [8] Inhibition of RAS activation due to a homozygous ezrin variant in patients with profound intellectual disability. Hum Mutat. 2015 Feb;36(2):270-8. doi: 10.1002/humu.22737.
• [9] A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am J Hum Genet. 2007 Oct;81(4):792-8. doi: 10.1086/521275. Epub 2007 Aug 31.
• [10] Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. Am J Hum Genet. 2018 Jan 4;102(1):175-187. doi: 10.1016/j.ajhg.2017.11.013. Epub 2017 Dec 21.
• [11] Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science. 2002 Nov 29;298(5599):1779-81. doi: 10.1126/science.1076521.
• [12] A null mutation in TNIK defines a novel locus for intellectual disability. Hum Genet. 2016 Jul;135(7):773-8. doi: 10.1007/s00439-016-1671-9. Epub 2016 Apr 22.
• [13] SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. Brain. 2020 Aug 1;143(8):2380-2387. doi: 10.1093/brain/awaa176.
• [14] Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy. Am J Hum Genet. 2017 May 4;100(5):824-830.
• [15] Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Hum Mol Genet. 2015 Oct 15;24(20):5697-710. doi: 10.1093/hmg/ddv286. Epub 2015 Jul 23.
• [16] Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration. Eur J Hum Genet. 2016 Mar;24(3):392-9. doi: 10.1038/ejhg.2015.148. Epub 2015 Jul 15.
• [17] Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification. Am J Hum Genet. 2019 Jun 6;104(6):1202-1209. doi: 10.1016/j.ajhg.2019.03.026. Epub 2019 May 9.
• [18] B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies. Genome Med. 2017 Dec 22;9(1):118. doi: 10.1186/s13073-017-0505-2.
• [19] The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet. 2006 Mar;43(3):203-10. doi: 10.1136/jmg.2005.035709. Epub 2005 Jul 20.
• [20] A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability. Eur J Hum Genet. 2015 Mar;23(3):331-6. doi: 10.1038/ejhg.2014.13. Epub 2014 Feb 26.
• [21] Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. doi: 10.1371/journal.pone.0028936. Epub 2012 Jan 17.
• [22] Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family. Hum Genet. 2014 Aug;133(8):975-84. doi: 10.1007/s00439-014-1438-0. Epub 2014 Mar 13.
• [23] Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability. Am J Hum Genet. 2014 Dec 4;95(6):721-8. doi: 10.1016/j.ajhg.2014.10.016.
• [24] AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability. Nat Commun. 2017 Jul 4;8:15910. doi: 10.1038/ncomms15910.
• [25] Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. Am J Hum Genet. 2019 Nov 7;105(5):907-920. doi: 10.1016/j.ajhg.2019.09.013. Epub 2019 Oct 10.
• [26] LINS, a modulator of the WNT signaling pathway, is involved in human cognition. Orphanet J Rare Dis. 2013 Jun 17;8:87. doi: 10.1186/1750-1172-8-87.
• [27] Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family. J Med Genet. 2016 Feb;53(2):138-44. doi: 10.1136/jmedgenet-2015-103179. Epub 2015 Nov 13.
• [28] Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2011 Jul 15;89(1):176-82. doi: 10.1016/j.ajhg.2011.06.006.
• [29] Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet. 2016 Oct 6;99(4):912-916. doi: 10.1016/j.ajhg.2016.07.019. Epub 2016 Sep 8.
• [30] MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science. 2011 Aug 26;333(6046):1161-3. doi: 10.1126/science.1206638.
• [31] Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. J Med Genet. 2015 Feb;52(2):123-7. doi: 10.1136/jmedgenet-2014-102793. Epub 2014 Dec 19.
• [32] Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability. Hum Mol Genet. 2014 Aug 1;23(15):4015-23. doi: 10.1093/hmg/ddu115. Epub 2014 Mar 13.
• [33] Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy. Am J Hum Genet. 2021 Apr 1;108(4):739-748. doi: 10.1016/j.ajhg.2021.02.015. Epub 2021 Mar 11.
• [34] NDST1 missense mutations in autosomal recessive intellectual disability. Am J Med Genet A. 2014 Nov;164A(11):2753-63. doi: 10.1002/ajmg.a.36723. Epub 2014 Aug 14.
• [35] Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet. 2012 May 4;90(5):847-55. doi: 10.1016/j.ajhg.2012.03.021. Epub 2012 Apr 26.
• [36] Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet. 2014 May 1;10(5):e1004320. doi: 10.1371/journal.pgen.1004320. eCollection 2014 May.
• [37] Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J Med Genet. 2017 Mar;54(3):196-201. doi: 10.1136/jmedgenet-2016-104202. Epub 2016 Sep 30.
• [38] GWAS signals revisited using human knockouts. Genet Med. 2018 Jan;20(1):64-68. doi: 10.1038/gim.2017.78. Epub 2017 Jun 22.
• [39] Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Hum Mutat. 2017 Jun;38(6):621-636. doi: 10.1002/humu.23205. Epub 2017 Mar 23.
• [40] ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet. 2011 Sep 9;89(3):407-14. doi: 10.1016/j.ajhg.2011.08.008.
• [41] Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum Mol Genet. 2011 Apr 1;20(7):1285-9. doi: 10.1093/hmg/ddq569. Epub 2011 Jan 6.
• [42] Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet. 2009 Dec;85(6):909-15. doi: 10.1016/j.ajhg.2009.11.009.
• [43] Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability. J Med Genet. 2021 Apr;58(4):237-246. doi: 10.1136/jmedgenet-2020-106849. Epub 2020 May 21.