Details of Disease

General Information of Disease (ID: DIS71AI3)

• Disease Name: Non-syndromic X-linked intellectual disability
• Synonyms: isolated X-linked intellectual disability; X-linked non-specific intellectual disability; X-linked non-syndromic intellectual disability; nonsyndromic X-linked intellectual disability; intellectual disability, X-linked, nonsyndromic; non-syndromic intellectual disability, X-linked; intellectual disability, nonsyndromic, X-linked; mental retardation, X-linked, nonsyndromic; mental retardation, nonsyndromic, X-linked; non-specific X-linked intellectual disability; non-specific X-linked mental retardation; non-syndromic X-linked intellectual disability
• Definition: Nonspecific X-linked intellectual deficiencies (MRX) belong to the family of sex-linked intellectual deficiencies (XLMR). In contrast to syndromic or specific X-linked intellectual deficiencies (MRXS), which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only symptom of MRX.
• Disease Hierarchy:
  DISTFIZ6: Non-syndromic intellectual disability
  DISYJBY3: X-linked intellectual disability
  DIS71AI3: Non-syndromic X-linked intellectual disability
• Disease Identifiers:
  MONDO ID: MONDO_0019181
  MESH ID: C564490
  UMLS CUI: C3501611
  MedGen ID: 502019
  Orphanet ID: 777

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 34 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ZNF41	OT501LXA	Disputed	X-linked	[1]
UPF3B	OTSI7RMZ	Supportive	X-linked	[2]
USP27X	OT9LZUX6	Supportive	X-linked	[3]
USP9X	OT9ASQSE	Supportive	X-linked	[4]
ZNF711	OT2IV5P4	Supportive	X-linked	[5]
ZNF81	OT55BMLW	Supportive	X-linked	[6]
AGTR2	OTU8GU9M	Supportive	X-linked	[8]
ALG13	OTOH9PMY	Supportive	X-linked	[13]
ARHGEF6	OTN1ABGL	Supportive	X-linked	[14]
ARX	OTBGYH25	Supportive	X-linked	[15]
CNKSR2	OTAGERJ2	Supportive	X-linked	[3]
DMD	OTD21T5J	Supportive	X-linked	[9]
FRMPD4	OT60SNXQ	Supportive	X-linked	[3]
FTSJ1	OTNE7W96	Supportive	X-linked	[16]
HCFC1	OT0UCK62	Supportive	X-linked	[17]
IQSEC2	OTYFRM4Q	Supportive	X-linked	[18]
MECP2	OTREZK68	Supportive	X-linked	[10]
MID2	OTAAQNZA	Supportive	X-linked	[19]
PAK3	OT80M3BV	Supportive	X-linked	[20]
RAB39B	OTDCLLT0	Supportive	X-linked	[21]
RPS6KA3	OTYJNNMD	Supportive	X-linked	[11]
SLC9A7	OTVDLTYA	Supportive	X-linked	[12]
GDI1	OTYM3928	Moderate	X-linked	[1]
SYP	OTFJKMO4	Moderate	X-linked	[1]
TSPAN7	OTE4DJ79	Moderate	X-linked	[1]
ACSL4	OTI71MUJ	Definitive	X-linked	[1]
AFF2	OTMF1PZW	Definitive	X-linked	[1]
AP1S2	OTZHJFYI	Definitive	Biomarker	[22]
CLCN4	OT4A2UWF	Definitive	X-linked	[1]
DLG3	OTH591WK	Definitive	X-linked	[1]
HUWE1	OTFH6BJS	Definitive	X-linked	[1]
IL1RAPL1	OTW3T4B2	Definitive	X-linked	[1]
PTCHD1	OTFDLU5S	Definitive	X-linked	[1]
RLIM	OTEBRNHJ	Definitive	X-linked	[23]

This Disease Is Related to 6 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
AGTR2	TTQVOEI	Disputed	Biomarker	[7]
AGTR2	TTQVOEI	Supportive	X-linked	[8]
DMD	TT2TNRM	Supportive	X-linked	[9]
MECP2	TTTAU9R	Supportive	X-linked	[10]
RPS6KA3	TTUM2ZR	Supportive	X-linked	[11]
TSPAN7	TTMT6VE	Moderate	X-linked	[1]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC9A7	DTQPK6R	Supportive	X-linked	[12]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet. 2007 Sep;39(9):1127-33. doi: 10.1038/ng2100. Epub 2007 Aug 19.
• [3] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [4] Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. Am J Hum Genet. 2014 Mar 6;94(3):470-8. doi: 10.1016/j.ajhg.2014.02.004.
• [5] A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet. 2009 May;41(5):535-43. doi: 10.1038/ng.367. Epub 2009 Apr 19.
• [6] Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation. J Med Genet. 2004 May;41(5):394-9. doi: 10.1136/jmg.2003.016972.
• [7] XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet. 2013 Aug 8;93(2):368-83. doi: 10.1016/j.ajhg.2013.06.013. Epub 2013 Jul 18.
• [8] Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation. Hum Genet. 2004 Jan;114(2):211-3. doi: 10.1007/s00439-003-1048-8. Epub 2003 Nov 4.
• [9] A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy. Eur J Hum Genet. 2014 Apr;22(4):480-5. doi: 10.1038/ejhg.2013.169. Epub 2013 Jul 31.
• [10] MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001 Apr 15;10(9):941-6. doi: 10.1093/hmg/10.9.941.
• [11] Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. Clin Genet. 2006 Dec;70(6):509-15. doi: 10.1111/j.1399-0004.2006.00723.x.
• [12] A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation. Hum Mol Genet. 2019 Feb 15;28(4):598-614. doi: 10.1093/hmg/ddy371.
• [13] X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings. Am J Med Genet A. 2014 Jan;164A(1):164-9. doi: 10.1002/ajmg.a.36233.
• [14] Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet. 2000 Oct;26(2):247-50. doi: 10.1038/80002.
• [15] XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. BMC Med Genet. 2005 Apr 25;6:16. doi: 10.1186/1471-2350-6-16.
• [16] A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):479-84. doi: 10.1002/ajmg.b.30638.
• [17] A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am J Hum Genet. 2012 Oct 5;91(4):694-702. doi: 10.1016/j.ajhg.2012.08.011. Epub 2012 Sep 20.
• [18] Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet. 2010 Jun;42(6):486-8. doi: 10.1038/ng.588. Epub 2010 May 16.
• [19] Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India. Hum Mutat. 2014 Jan;35(1):41-4. doi: 10.1002/humu.22453. Epub 2013 Oct 21.
• [20] A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. Eur J Hum Genet. 2008 Nov;16(11):1358-63. doi: 10.1038/ejhg.2008.103. Epub 2008 Jun 4.
• [21] Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet. 2010 Feb 12;86(2):185-95. doi: 10.1016/j.ajhg.2010.01.011.
• [22] AP-1/1A and AP-1/1B adaptor-proteins differentially regulate neuronal early endosome maturation via the Rab5/Vps34-pathway.Sci Rep. 2016 Jul 14;6:29950. doi: 10.1038/srep29950.
• [23] Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. Eur J Hum Genet. 2015 Dec;23(12):1652-6. doi: 10.1038/ejhg.2015.30. Epub 2015 Mar 4.