NEXMIF

Summary

NEXMIF (neurite extension and migration factor, HGNC:29433) is a protein-coding gene on chromosome Xq13.3, encoding Neurite extension and migration factor (Q5QGS0). Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway. It is haploinsufficient (ClinGen: sufficient evidence).

An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.

Source: NCBI Gene 340533 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 1,349 total — 197 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 108
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001008537

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29433
Approved symbol	NEXMIF
Name	neurite extension and migration factor
Location	Xq13.3
Locus type	gene with protein product
Status	Approved
Aliases	XPN, MRX98, KIDLIA
Ensembl gene	ENSG00000050030
Ensembl biotype	protein_coding
OMIM	300524
Entrez	340533

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000055682, ENST00000616200, ENST00000642681

RefSeq mRNA: 1 — MANE Select: NM_001008537 NM_001008537

CCDS: CCDS35337

Canonical transcript exons

ENST00000055682 — 4 exons

Exon	Start	End
ENSE00000388714	74740100	74744477
ENSE00001292773	74924883	74925452
ENSE00001313509	74745572	74745697
ENSE00001460638	74732856	74739498

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 97.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2427 / max 13.0241, expressed in 105 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199772	0.2427	105

Top tissues by expression

237 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.39	gold quality
buccal mucosa cell	CL:0002336	88.42	silver quality
Brodmann (1909) area 46	UBERON:0006483	88.10	gold quality
cortical plate	UBERON:0005343	87.09	gold quality
entorhinal cortex	UBERON:0002728	86.60	gold quality
superior frontal gyrus	UBERON:0002661	82.76	gold quality
postcentral gyrus	UBERON:0002581	82.31	gold quality
parietal lobe	UBERON:0001872	81.85	gold quality
middle temporal gyrus	UBERON:0002771	81.45	gold quality
primary visual cortex	UBERON:0002436	79.31	gold quality
ganglionic eminence	UBERON:0004023	78.96	gold quality
cerebellar vermis	UBERON:0004720	78.20	silver quality
occipital lobe	UBERON:0002021	78.12	gold quality
ventricular zone	UBERON:0003053	77.76	gold quality
islet of Langerhans	UBERON:0000006	74.22	gold quality
cartilage tissue	UBERON:0002418	74.10	gold quality
cerebral cortex	UBERON:0000956	71.93	gold quality
prefrontal cortex	UBERON:0000451	71.88	gold quality
temporal lobe	UBERON:0001871	71.87	gold quality
epithelial cell of pancreas	CL:0000083	71.52	silver quality
frontal cortex	UBERON:0001870	71.45	gold quality
neocortex	UBERON:0001950	71.12	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.58	gold quality
bronchial epithelial cell	CL:0002328	70.45	gold quality
superior vestibular nucleus	UBERON:0007227	70.44	gold quality
bronchus	UBERON:0002185	69.30	gold quality
cauda epididymis	UBERON:0004360	68.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	68.91	silver quality
Ammon’s horn	UBERON:0001954	68.32	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

483 targeting NEXMIF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• disrupted in X-linked mental retardation (PMID:15466006)
• study describes 3 new families with likely pathogenic mutations of KIAA2022 and further defined clinical and genetic phenotypes; role of KIAA2022 in neuronal development, together with the clinical features of patients observed, provides evidence that KIAA2022 is essential for proper brain development (PMID:23615299)
• Xpn regulates cell-cell and cell-matrix adhesion and cellular migration by regulating the expression of adhesion molecules (PMID:24071057)
• Two unrelated patients with X-linked intellectual disability found having the KIAA2022 mutation phenotype. (PMID:25900396)
• Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy. (PMID:27358180)
• This study supports KIAA2022 as a novel cause of X-linked dominant intellectual disability, and broadens the phenotype for KIAA2022 mutations. (PMID:27568816)
• Clinical spectrum of KIAA2022 pathogenic variants in males.[review] (PMID:29693785)
• This is a study of the novel NEXMIF pathogenic variant in a boy with severe autistic features, intellectual disability, and epilepsy, and his mildly affected mother. (PMID:29717186)
• Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients. (PMID:32600841)
• NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. (PMID:33144681)
• Clinical evaluation of torpedo maculopathy in an infant population with additional genetic testing for NEXMIF mutation. (PMID:34326501)
• NEXMIF pathogenic variants in individuals of Korean, Vietnamese, and Mexican descent. (PMID:35146903)
• NEXMIF mutations in intellectual disability and epilepsy: A report of 2 cases and literature review.", trans “NEXMIF2. (PMID:35545418)
• [Epilepsy and other phenotypic features of X-linked intellectual disability caused by the mutations in the KIAA2022 gene].”, trans “Epilepsiya i drugie fenotipicheskie osobennosti X-stseplennoi intellektual’noi nedostatochnosti, obuslovlennoi mutatsiyami gena KIAA2022. (PMID:36170093)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nexmifb	ENSDARG00000029296
danio_rerio	nexmifa	ENSDARG00000089271
mus_musculus	Nexmif	ENSMUSG00000046449
rattus_norvegicus	Nexmif	ENSRNOG00000021589
drosophila_melanogaster	PolZ1	FBGN0002891
caenorhabditis_elegans		WBGENE00021344

Paralogs (3): REV3L (ENSG00000009413), POLD1 (ENSG00000062822), POLA1 (ENSG00000101868)

Protein

Protein identifiers

Neurite extension and migration factor — Q5QGS0 (reviewed: Q5QGS0)

Alternative names: XLMR protein related to neurite extension

All UniProt accessions (2): A0A2R8YEQ5, Q5QGS0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway. May act by regulating expression of protein-coding genes, such as N-cadherins and integrin beta-1 (ITGB1).

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Highly expressed in fetal and adult brain, predominantly in the cerebral cortex and the cerebellum. Also expressed in other tissues but to a lesser extent.

Disease relevance. Intellectual developmental disorder, X-linked 98 (XLID98) [MIM:300912] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. XLID98 patients show delayed psychomotor development, absent or poor speech development, and postnatal growth retardation, often with microcephaly. Some patients show autistic behavioral features, such as stereotypic hand movements and repetitive behaviors. Additional, more variable features include spasticity, axial hypotonia, seizures, drooling, gastroesophageal reflux, and lack of sphincter control. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving NEXMIF is found in patients with severe intellectual disability. Pericentric inversion inv(X)(p22.3;q13.2) with P2RY8 leading to inactivation of NEXMIF. XLID98 transmission pattern is consistent with X-linked recessive inheritance. In some cases, de novo heterozygous loss-of-function mutations have been found in affected females, while some female carriers are asymptomatic. The female phenotype partially overlaps with the reported male phenotype but includes epilepsy as a relevant feature. The variability of disease manifestation in female carriers is probably due to skewed X inactivation with differential expression in the brain.

RefSeq proteins (1): NP_001008537* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032757	DUF4683	Domain
IPR042794	Nexmif	Family

Pfam: PF15735

UniProt features (20 total): sequence variant 8, compositionally biased region 6, region of interest 5, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5QGS0-F1	40.87	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 478 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, AAGTCCA_MIR422B_MIR422A, TTTGTAG_MIR520D, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_NEUROGENESIS, CACCAGC_MIR138, GCGCTTT_MIR518B_MIR518C_MIR518D, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION, GOBP_CELL_CELL_ADHESION, AGCGCTT_MIR518F_MIR518E_MIR518A, GOBP_NEGATIVE_REGULATION_OF_CELL_MATRIX_ADHESION

GO Biological Process (5): negative regulation of cell-matrix adhesion (GO:0001953), nervous system development (GO:0007399), negative regulation of cell adhesion mediated by integrin (GO:0033629), negative regulation of cell-cell adhesion mediated by cadherin (GO:2000048), negative regulation of neuron migration (GO:2001223)

GO Molecular Function (0):

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), midbody (GO:0030496), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
system development	1
negative regulation of cell adhesion	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
negative regulation of cell-cell adhesion	1
cell-cell adhesion mediated by cadherin	1
regulation of cell-cell adhesion mediated by cadherin	1
neuron migration	1
negative regulation of cell migration	1
regulation of neuron migration	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEXMIF	P2RY8	Q86VZ1	853
NEXMIF	RLIM	Q9NVW2	616
NEXMIF	ZDHHC15	Q96MV8	582
NEXMIF	TVP23A	A6NH52	478
NEXMIF	MAST2	Q6P0Q8	473
NEXMIF	ZC4H2	Q9NQZ6	466
NEXMIF	FAM47A	Q5JRC9	446
NEXMIF	EPHX4	Q8IUS5	438
NEXMIF	CCDC112	Q8NEF3	438
NEXMIF	SLC16A2	P36021	429
NEXMIF	CRLF2	Q9HC73	424
NEXMIF	CHIC1	Q5VXU3	406
NEXMIF	COP1	Q8NHY2	404
NEXMIF	NAA10	P41227	398
NEXMIF	CACNA1I	Q9P0X4	390

IntAct

2 interactions, top by confidence:

A	B	Type	Score
SCRIB	CHD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): KIAA2022 (Affinity Capture-MS), NARS (Cross-Linking-MS (XL-MS)), KIAA2022 (Cross-Linking-MS (XL-MS)), KIAA2022 (Cross-Linking-MS (XL-MS)), KIAA2022 (Cross-Linking-MS (XL-MS)), CPNE1 (Cross-Linking-MS (XL-MS)), KIAA2022 (Cross-Linking-MS (XL-MS)), KIAA2022 (Cross-Linking-MS (XL-MS)), KIAA2022 (Affinity Capture-MS), KIAA2022 (Affinity Capture-MS), KIAA2022 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WRU1, A0JNH1, A2RUB1, A6QNQ6, B0S6S9, B1WC58, D3Z987, D3ZJ47, E1BC15, O60673, P28358, P28359, P56716, P70347, Q0P5X5, Q0VAV2, Q0VBV7, Q15468, Q2M2Z5, Q3UXL4, Q3V089, Q49A88, Q569L8, Q5BQN8, Q5CZC0, Q5QGS0, Q5T1N1, Q5VWN6, Q60988, Q61493, Q62924, Q6ZP01, Q6ZU52, Q6ZVD7, Q80U59, Q80WQ8, Q86WS4, Q86YC2, Q8CB14, Q8IUR6

Diamond homologs: D3ZGX1, O60673, Q5DTT1, Q5QGS0, Q61493, O48901, P14284, P90829, Q5TGY3, Q6PAL7, Q766Z3, Q85428, Q9GSR1, Q9LVN7, Q9P6L6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NEXMIF	up-regulates	Neurite_outgrowth
NEXMIF	“up-regulates quantity by expression”	CDH2	“transcriptional regulation”
NEXMIF	“up-regulates quantity by expression”	ITGB1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1349 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	197
Likely pathogenic	26
Uncertain significance	611
Likely benign	251
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012179	NM_001008537.3(NEXMIF):c.1752_1761del (p.Leu584fs)	Pathogenic
1012662	NM_001008537.3(NEXMIF):c.568_569dup (p.Asn192fs)	Pathogenic
1033187	NM_001008537.3(NEXMIF):c.1159G>T (p.Glu387Ter)	Pathogenic
1033191	NM_001008537.3(NEXMIF):c.862G>T (p.Glu288Ter)	Pathogenic
1068655	NM_001008537.3(NEXMIF):c.1783A>T (p.Arg595Ter)	Pathogenic
1069937	NM_001008537.3(NEXMIF):c.1437del (p.Leu480fs)	Pathogenic
1071637	NM_001008537.3(NEXMIF):c.1350T>G (p.Tyr450Ter)	Pathogenic
1072361	NM_001008537.3(NEXMIF):c.2274_2278del (p.Asn758fs)	Pathogenic
1073587	NM_001008537.3(NEXMIF):c.3314_3321del (p.Pro1105fs)	Pathogenic
1074733	NM_001008537.3(NEXMIF):c.2816del (p.Asn939fs)	Pathogenic
1075288	NM_001008537.3(NEXMIF):c.1044dup (p.Glu349fs)	Pathogenic
1075962	NM_001008537.3(NEXMIF):c.1084dup (p.Ser362fs)	Pathogenic
1076827	NM_001008537.3(NEXMIF):c.2799C>A (p.Tyr933Ter)	Pathogenic
1285547	NM_001008537.3(NEXMIF):c.1763G>A (p.Trp588Ter)	Pathogenic
1299508	NM_001008537.3(NEXMIF):c.3409C>T (p.Gln1137Ter)	Pathogenic
1319375	NM_001008537.3(NEXMIF):c.1349del (p.Tyr450fs)	Pathogenic
1323146	NM_001008537.3(NEXMIF):c.2714C>G (p.Ser905Ter)	Pathogenic
1325629	NM_001008537.3(NEXMIF):c.3700G>T (p.Gly1234Ter)	Pathogenic
1334563	NM_001008537.3(NEXMIF):c.792_795del (p.Phe264fs)	Pathogenic
1335779	NM_001008537.3(NEXMIF):c.3709dup (p.Met1237fs)	Pathogenic
1338811	NM_001008537.3(NEXMIF):c.3579del (p.Asn1195fs)	Pathogenic
1343234	NM_001008537.3(NEXMIF):c.643G>T (p.Gly215Ter)	Pathogenic
1366791	NM_001008537.3(NEXMIF):c.1629_1635dup (p.Asn546delinsHisHisTer)	Pathogenic
1367507	NM_001008537.3(NEXMIF):c.2625del (p.His876fs)	Pathogenic
1374270	NM_001008537.3(NEXMIF):c.2123_2124del (p.Glu708fs)	Pathogenic
1398402	NM_001008537.3(NEXMIF):c.2656A>T (p.Arg886Ter)	Pathogenic
1428016	NM_001008537.3(NEXMIF):c.2938C>T (p.Gln980Ter)	Pathogenic
1429901	NM_001008537.3(NEXMIF):c.3026T>G (p.Leu1009Ter)	Pathogenic
1432109	NM_001008537.3(NEXMIF):c.2536dup (p.Thr846fs)	Pathogenic
1432127	NM_001008537.3(NEXMIF):c.2835C>A (p.Cys945Ter)	Pathogenic

SpliceAI

1344 predictions. Top by Δscore:

Variant	Effect	Δscore
X:74744473:TGAGT:T	acceptor_gain	1.0000
X:74744476:GT:G	acceptor_gain	1.0000
X:74744478:C:CC	acceptor_gain	1.0000
X:74744478:C:CG	acceptor_loss	1.0000
X:74745566:CCTT:C	donor_loss	1.0000
X:74745567:CTTAC:C	donor_loss	1.0000
X:74745568:TTACC:T	donor_loss	1.0000
X:74745569:T:TG	donor_loss	1.0000
X:74745570:A:AC	donor_gain	1.0000
X:74745571:C:CC	donor_gain	1.0000
X:74745698:C:CC	acceptor_gain	1.0000
X:74745698:CT:C	acceptor_loss	1.0000
X:74769525:T:TA	donor_gain	1.0000
X:74744474:GAGT:G	acceptor_gain	0.9900
X:74744475:AGT:A	acceptor_gain	0.9900
X:74745693:CCAAC:C	acceptor_gain	0.9900
X:74745694:CAAC:C	acceptor_gain	0.9900
X:74745694:CAACC:C	acceptor_gain	0.9900
X:74748742:AGAT:A	donor_gain	0.9900
X:74769497:C:CT	donor_gain	0.9900
X:74769498:T:TT	donor_gain	0.9900
X:74769521:T:TA	donor_gain	0.9900
X:74924879:TCAC:T	donor_loss	0.9900
X:74924880:CAC:C	donor_loss	0.9900
X:74739404:A:C	donor_gain	0.9800
X:74739416:T:A	donor_gain	0.9800
X:74745570:AC:A	donor_gain	0.9800
X:74745571:CC:C	donor_gain	0.9800
X:74745708:CAAA:C	acceptor_loss	0.9800
X:74748745:T:TA	donor_gain	0.9800

AlphaMissense

10152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:74743628:A:G	L310P	1.000
X:74743733:A:G	L275P	1.000
X:74743742:A:G	L272P	1.000
X:74740589:A:T	I1323N	0.999
X:74740598:A:G	L1320S	0.999
X:74742914:A:G	F548S	0.999
X:74742917:C:G	R547P	0.999
X:74742926:A:T	I544N	0.999
X:74743105:T:A	R484S	0.999
X:74743105:T:G	R484S	0.999
X:74743606:A:C	F317L	0.999
X:74743606:A:T	F317L	0.999
X:74743607:A:G	F317S	0.999
X:74743608:A:G	F317L	0.999
X:74743619:C:G	R313P	0.999
X:74743622:A:C	I312S	0.999
X:74743622:A:G	I312T	0.999
X:74743622:A:T	I312N	0.999
X:74743703:A:G	L285P	0.999
X:74743729:A:C	C276W	0.999
X:74743731:A:G	C276R	0.999
X:74743739:A:G	L273P	0.999
X:74740559:A:G	F1333S	0.998
X:74740580:C:T	G1326D	0.998
X:74740581:C:G	G1326R	0.998
X:74740586:G:T	A1324D	0.998
X:74740589:A:C	I1323S	0.998
X:74740598:A:C	L1320W	0.998
X:74741393:A:T	I1055K	0.998
X:74742913:A:C	F548L	0.998

dbSNP variants (sampled 300 via entrez): RS1000008073 (X:74766278 A>G), RS1000081120 (X:74899039 T>C), RS1000113295 (X:74845072 A>G), RS1000120590 (X:74892424 A>C), RS1000162005 (X:74798209 A>G), RS1000180090 (X:74908298 G>A,T), RS1000217280 (X:74847960 CCTT>C), RS1000244913 (X:74852930 G>A), RS1000248267 (X:74791730 A>T), RS1000251302 (X:74879391 A>G), RS1000278525 (X:74797542 G>A), RS1000295796 (X:74764895 T>G), RS1000299865 (X:74860466 C>T), RS1000316236 (X:74907958 C>T), RS1000328289 (X:74746363 C>T)

Disease associations

OMIM: gene MIM:300524 | disease phenotypes: MIM:300912

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	X-linked
X-linked intellectual disability, Cantagrel type	Strong	X-linked
myoclonic-astatic epilepsy	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (5): X-linked intellectual disability, Cantagrel type (MONDO:0010483), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), X-linked complex neurodevelopmental disorder (MONDO:0100148), (MONDO:0016025)

Orphanet (2): X-linked intellectual disability, Cantagrel type (Orphanet:85277), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000049	Shawl scrotum
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000289	Broad philtrum
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000565	Esotropia
HP:0000568	Microphthalmia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008161_49	Waist circumference adjusted for body mass index	4.000000e-06
GCST009391_1866	Metabolite levels	9.000000e-06
GCST90002397_159	Mean spheric corpuscular volume	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0010410	triacylglycerol 50:3 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	increases methylation, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
belinostat	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Lead	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

298 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study