NFIX

Summary

NFIX (nuclear factor I X, HGNC:7788) is a protein-coding gene on chromosome 19p13.13, encoding Nuclear factor 1 X-type (Q14938). Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3 in viral and cellular promoters. The encoded protein can also stimulate adenovirus replication in vitro. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4784 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Marshall-Smith syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 30
• Clinical variants (ClinVar): 521 total — 116 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 202
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 29 downstream targets (CollecTRI)
• MANE Select transcript: NM_001365902

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7788
Approved symbol	NFIX
Name	nuclear factor I X
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	NF1A
Ensembl gene	ENSG00000008441
Ensembl biotype	protein_coding
OMIM	164005
Entrez	4784

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000358552, ENST00000360105, ENST00000397661, ENST00000585382, ENST00000585575, ENST00000586797, ENST00000586873, ENST00000587260, ENST00000587760, ENST00000588228, ENST00000588680, ENST00000590027, ENST00000591028, ENST00000592199, ENST00000622520, ENST00000676441, ENST00000693124

RefSeq mRNA: 10 — MANE Select: NM_001365902 NM_001271043, NM_001271044, NM_001365902, NM_001365982, NM_001365983, NM_001365984, NM_001365985, NM_001378404, NM_001378405, NM_002501

CCDS: CCDS45996, CCDS59359, CCDS92530, CCDS92531, CCDS92532, CCDS92533

Canonical transcript exons

ENST00000592199 — 11 exons

Exon	Start	End
ENSE00003480560	13078613	13078735
ENSE00003488314	13087989	13088136
ENSE00003525435	13073906	13074026
ENSE00003567637	13073422	13073496
ENSE00003585342	13075535	13075671
ENSE00003591998	13081680	13081855
ENSE00003634013	13073047	13073109
ENSE00003636536	13090299	13090390
ENSE00003674153	13025021	13025552
ENSE00003908028	12995475	12995864
ENSE00003909140	13094635	13098796

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.3560 / max 705.5640, expressed in 1568 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174076	28.7218	1533
174089	4.9101	660
174094	2.7576	407
174088	2.2892	741
174091	1.8971	340
174101	1.0527	494
174103	0.9483	517
174077	0.7205	361
174093	0.6181	176
174095	0.5480	190

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.27	gold quality
nipple	UBERON:0002030	99.17	gold quality
ganglionic eminence	UBERON:0004023	98.88	gold quality
inferior vagus X ganglion	UBERON:0005363	98.68	gold quality
medial globus pallidus	UBERON:0002477	98.58	gold quality
postcentral gyrus	UBERON:0002581	98.58	gold quality
parietal lobe	UBERON:0001872	98.56	gold quality
ventral tegmental area	UBERON:0002691	98.48	gold quality
tendon of biceps brachii	UBERON:0008188	98.47	gold quality
buccal mucosa cell	CL:0002336	98.45	gold quality
globus pallidus	UBERON:0001875	98.32	gold quality
cardia of stomach	UBERON:0001162	98.31	gold quality
urethra	UBERON:0000057	98.11	gold quality
ventricular zone	UBERON:0003053	98.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.03	gold quality
cerebellar hemisphere	UBERON:0002245	97.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.95	gold quality
cerebellar cortex	UBERON:0002129	97.93	gold quality
mammary duct	UBERON:0001765	97.87	gold quality
pylorus	UBERON:0001166	97.52	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.45	gold quality
subthalamic nucleus	UBERON:0001906	97.36	gold quality
saphenous vein	UBERON:0007318	97.36	gold quality
mammalian vulva	UBERON:0000997	97.34	gold quality
cerebellum	UBERON:0002037	97.21	gold quality
lateral globus pallidus	UBERON:0002476	97.19	gold quality
body of tongue	UBERON:0011876	96.92	gold quality
vena cava	UBERON:0004087	96.90	gold quality
gastrocnemius	UBERON:0001388	96.81	gold quality
right coronary artery	UBERON:0001625	96.72	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	240.12
E-MTAB-9221	yes	18.03
E-ANND-3	yes	16.23
E-MTAB-9467	yes	4.29

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

29 targets.

Target	Regulation
ANOS1	Repression
CCL2	Activation
CDKN1A	Repression
CGGBP1
CHI3L1	Activation
CKM
CYP3A7	Repression
ENO3
EPHA4	Activation
EPHA5	Activation
EPHA8	Activation
ETV5	Repression
FOXO6	Repression
GAS6	Repression
GFAP
HGF	Repression
HSF1	Unknown
ID3	Repression
NEUROD1	Activation
NEUROD4	Activation
NFIX
PITX2
RBFOX3	Activation
REN	Repression
ROBO1	Activation
SLIT1	Activation
SOX9	Repression
SPARCL1
WNT5A	Repression

JASPAR motifs

Motif	Name	Family
MA0671.1	NFIX	Nuclear factor 1
MA0671.2	NFIX	Nuclear factor 1
MA1528.1	NFIX	Nuclear factor 1
MA1528.2	NFIX	Nuclear factor 1

JASPAR matrix evidence (PMIDs): PMID:20178747, PMID:22456058

Upstream regulators (CollecTRI, top): HSF1, NFIA, NFIB, NFIX

miRNA regulators (miRDB)

215 targeting NFIX, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 39)

• NFI-X cooperates with (activator protein 1)AP-1 by an unknown mechanism in astrocytes, which results in the expression of a subset of astrocyte-specific genes. (PMID:16565071)
• temporal and dose-dependent interference by an AP-1 family member, c-Jun, upon NF-1 proteins binding an NF-1 consensus site derived from JC virus promoter sequence (PMID:16928756)
• First report of structural alterations of the NFIA gene in hematopoietic diseases (polycythemia vera and chronic myelomonocytic leukemia, type 1). (PMID:18754024)
• an expression program of NFIs is executed during the differentiation of astrocytes, with NFI-X and -C controlling the expression of astrocytic markers at late stages of differentiation. (PMID:19418463)
• Nuclear factor IA may play a role in astrocytoma biology. (PMID:20150379)
• These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on nonsense-mediated mRNA decay. (PMID:20673863)
• NFI-X3 activates GFAP expression, in part, by inducing alterations in the nucleosome architecture that lead to the increased recruitment of RNA polymerase II (PMID:21189253)
• NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression. (PMID:21953450)
• missense mutations in NFIX were able to cause Sotos-like features. (PMID:22301465)
• DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. (PMID:22422452)
• Deletions in the 3’ part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome. (PMID:24924640)
• NFIX analysis should be considered in patients presenting with overgrowth, macrocephaly and developmental delay including those in whom Sotos syndrome has been considered clinically but are negative for pathogenic NSD1 variants. (PMID:25118028)
• TGF-beta-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence. (PMID:25220407)
• Report novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome. (PMID:26200704)
• Plasma miR-1914* and -1915 interact with NFIX RNA. (PMID:26695693)
• Studies indicate the role of nuclear factor one (NFIs) as epigenetic regulators in cancer. (PMID:28076901)
• A novel de novo pathogenic variant in the NFIX gene identified in a case of Marshall-Smith syndrome with precocious puberty and aortic root dilatation. (PMID:28442439)
• Compared to noncancerous esophageal mucosa, miR-1290 expression was upregulated, while NFIX mRNA expression was downregulated in ESCC tissues. Data suggest that the dysregulation of miR-1290-NFIX axis may play crucial roles in esophageal carcinogenesis and progression. (PMID:28800311)
• Microduplications encompassing NFIX cause intellectual disability, short stature and small head circumference. (PMID:29184170)
• Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation (PMID:29897170)
• Data show that miR-744-5p expression directly downregulated mRNA and protein expression of nuclear factor I X (NFIX) and heterogeneous nuclear ribonucleoprotein C (HNRNPC). (PMID:29899543)
• We identified recurrent targeting of NFIX by HPV16 insertion in anal carcinomas, supporting a role for this gene in oncogenesis (PMID:30264502)
• It showing the contribution of NFIX to muscle development and muscular dystrophies, hematopoiesis, cancer, and neural stem cell biology, highlighting the importance of this knowledge in the development of therapeutic targets. (PMID:30287093)
• NFIX downregulation might independently predict poor prognosis in LUAD. DNA hypermethylation might be an important cause of the downregulation (PMID:30418046)
• Secretory carcinoma of the skin associated with the presence of novel NFIX-PKN1 translocation. (PMID:31045890)
• Malan syndrome due to shared NFIX variants was diagnosed in the brothers using exome sequencing. (PMID:31369202)
• Knockdown of circNFIX inhibits progression of glioma in vitro and in vivo by increasing miR-378e and decreasing RPN2, providing a novel mechanism for understanding the pathogenesis of glioma. (PMID:31888753)
• Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability. (PMID:32277047)
• A de-novo NFIX mutation causes a case of neonatal lethal Marshall-Smith syndrome. (PMID:32701632)
• Pathogenic variant in NFIX gene affecting three sisters due to paternal mosaicism. (PMID:32945093)
• A novel miRNA-762/NFIX pathway modulates LPS-induced acute lung injury. (PMID:34492536)
• CircNFIX regulates chondrogenesis and cartilage homeostasis by targeting the miR758-3p/KDM6A axis. (PMID:35791460)
• A Novel Tumor-Promoting Role for Nuclear Factor IX in Glioblastoma Is Mediated through Transcriptional Activation of GINS1. (PMID:36469009)
• CircNFIX stimulates the proliferation, invasion, and stemness properties of ovarian cancer cells by enhancing SH3RF3 mRNA stability via binding LIN28B. (PMID:36495291)
• NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate. (PMID:36901722)
• A rare cause of intellectual disability: Novel mutations of NFIX gene in two patients with clinical features of Marshall-Smith syndrome and Malan syndrome. (PMID:37336770)
• m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647. (PMID:37713785)
• [NFIX gene mutation causes Marshall-Smith syndrome in a pair of identical twins and literature review]. (PMID:39014953)
• Circular RNA NFIX Functions as an Oncogene in Non-Small Cell Lung Cancer by Modulating the miR-214-3p/TRIAP1 Axis. (PMID:39135128)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfixa	ENSDARG00000043226
danio_rerio	nfixb	ENSDARG00000061836
mus_musculus	Nfix	ENSMUSG00000001911
rattus_norvegicus	Nfix	ENSRNOG00000002983
drosophila_melanogaster	NfI	FBGN0042696
caenorhabditis_elegans		WBGENE00003592

Paralogs (3): NFIC (ENSG00000141905), NFIB (ENSG00000147862), NFIA (ENSG00000162599)

Protein

Protein identifiers

Nuclear factor 1 X-type — Q14938 (reviewed: Q14938)

Alternative names: CCAAT-box-binding transcription factor, Nuclear factor I/X, TGGCA-binding protein

All UniProt accessions (13): Q14938, A0A087WXP2, A0A8I5KYE6, A0A8J8YL86, B4DHW2, C9JWJ8, D2DXM9, K7EJB0, K7EKH0, K7EMQ5, K7EN08, K7EPU2, K7ESG9

UniProt curated annotations — full annotation on UniProt →

Function. Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.

Subunit / interactions. Binds DNA as a homodimer.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed.

Disease relevance. Malan syndrome (MALNS) [MIM:614753] An autosomal dominant syndrome characterized by overgrowth, advanced bone age, macrocephaly, impaired intellectual development, behavior anomalies, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly. The disease is caused by variants affecting the gene represented in this entry. Marshall-Smith syndrome (MRSHSS) [MIM:602535] A distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, intellectual disability, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. Additional skeletal findings include long and thin tubular bones, broad middle phalanges with relatively narrow distal phalanges, and scoliosis. Inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Similarity. Belongs to the CTF/NF-I family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q14938-1	1	yes
Q14938-2	2
Q14938-3	3
Q14938-4	4
Q14938-5	5
Q14938-6	6

RefSeq proteins (10): NP_001257972, NP_001257973, NP_001352831, NP_001352911, NP_001352912, NP_001352913, NP_001352914, NP_001365333, NP_001365334, NP_002492 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000647	CTF/NFI	Family
IPR003619	MAD_homology1_Dwarfin-type	Domain
IPR019548	CTF/NFI_DNA-bd_N	Domain
IPR019739	CTF/NFI_DNA-bd_CS	Conserved_site
IPR020604	CTF/NFI_DNA-bd-dom	Domain

Pfam: PF00859, PF03165, PF10524

UniProt features (43 total): helix 9, modified residue 7, sequence variant 6, splice variant 5, strand 4, region of interest 2, sequence conflict 2, turn 2, compositionally biased region 2, chain 1, DNA-binding region 1, cross-link 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9WA7	X-RAY DIFFRACTION	2.31
7QQD	X-RAY DIFFRACTION	2.7
7QQE	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14938-F1	62.94	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 301, 341, 343, 390, 279, 265, 280, 288

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-73980	RNA Polymerase III Transcription Termination
R-HSA-749476	RNA Polymerase III Abortive And Retractive Initiation

MSigDB gene sets: 764 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, YAATNRNNNYNATT_UNKNOWN, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, TGCACTT_MIR519C_MIR519B_MIR519A, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, NIKOLSKY_OVERCONNECTED_IN_BREAST_CANCER, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, TATTATA_MIR374, TGACCTY_ERR1_Q2, HNF1_Q6, FOXO1_01, CACCAGC_MIR138

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA replication (GO:0006260), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RNA Polymerase III Transcription	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
DNA metabolic process	1
DNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFIX	FOXA1	P55317	642
NFIX	SLC1A3	P43003	642
NFIX	CEBPZ	Q03701	593
NFIX	NSD1	Q96L73	586
NFIX	JUND	P17535	555
NFIX	NF1	P21359	538
NFIX	TP53	P04637	530
NFIX	HMGN1	P05114	502
NFIX	JUN	P05412	492
NFIX	NEUROD2	Q15784	491
NFIX	MBNL1	Q9NR56	477
NFIX	CLCN1	P35523	476
NFIX	CALR	P27797	466
NFIX	PIR	O00625	438
NFIX	NFIC	P08651	434

IntAct

44 interactions, top by confidence:

A	B	Type	Score
SMAD4	SMAD9	psi-mi:“MI:0914”(association)	0.750
NFIB	NFIC	psi-mi:“MI:0914”(association)	0.690
NFIC	NFIB	psi-mi:“MI:0914”(association)	0.690
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
NFIA	NFIB	psi-mi:“MI:0914”(association)	0.570
NFIX	NFIB	psi-mi:“MI:0914”(association)	0.570
NFIX	QRICH1	psi-mi:“MI:0915”(physical association)	0.560
NFIX	ZNF614	psi-mi:“MI:0915”(physical association)	0.560
ZNF614	NFIX	psi-mi:“MI:0915”(physical association)	0.560
QRICH1	NFIX	psi-mi:“MI:0915”(physical association)	0.560
NFIX	CREB1	psi-mi:“MI:0915”(physical association)	0.400
NFIX	NFIX	psi-mi:“MI:0915”(physical association)	0.370
	NFIX	psi-mi:“MI:0915”(physical association)	0.370
CCL8	NFIX	psi-mi:“MI:0915”(physical association)	0.370
TNFSF18	NFIX	psi-mi:“MI:0915”(physical association)	0.370
NFIX	JMJD6	psi-mi:“MI:0915”(physical association)	0.370
FOXA1	NFIC	psi-mi:“MI:0914”(association)	0.350
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
FOXN1	FOXN1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (802): NFIX (Two-hybrid), QRICH1 (Two-hybrid), ZNF614 (Two-hybrid), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-MS), NFIX (Affinity Capture-RNA), NFIX (Affinity Capture-RNA), NFIX (Two-hybrid)

ESM2 similar proteins: A1A4R9, A9CB91, O54835, O70436, P05549, P06435, P08651, P09286, P09414, P0C734, P11823, P11824, P13623, P17923, P19893, P21999, P30119, P34056, P42003, P58197, P70257, Q02780, Q09585, Q0ZME3, Q12857, Q14938, Q14EA6, Q15796, Q1HVD3, Q1W668, Q2T9K2, Q3KPS4, Q5R7C0, Q5RJ20, Q61312, Q61313, Q62432, Q6SW29, Q6SWP7, Q76HI7

Diamond homologs: O00712, P08651, P09414, P13622, P13623, P14057, P17923, P17924, P17926, P21999, P70255, P70257, P97863, Q02780, Q0VCL6, Q12857, Q14938, Q5H9N3, Q90932

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
FOXA1	up-regulates	NFIX	binding
NFIB	“down-regulates activity”	NFIX	binding
NFIX	“form complex”	PKCtheta/Nfix	binding
NFIB	“up-regulates quantity”	NFIX	“transcriptional regulation”
NFIA	“up-regulates quantity”	NFIX	“transcriptional regulation”
NFIX	“down-regulates quantity”	ANOS1	“transcriptional regulation”
NFIX	“down-regulates quantity”	ID3	“transcriptional regulation”
NFIX	“down-regulates quantity”	ETV5	“transcriptional regulation”
NFIX	“down-regulates quantity”	FOXO6	“transcriptional regulation”
NFIX	“down-regulates quantity”	GAS6	“transcriptional regulation”
NFIX	“down-regulates quantity”	WNT5A	“transcriptional regulation”
NFIX	“up-regulates quantity”	NEUROD1	“transcriptional regulation”
NFIX	“up-regulates quantity”	NEUROD4	“transcriptional regulation”
NFIX	“up-regulates quantity”	SLIT1	“transcriptional regulation”
NFIX	“up-regulates quantity”	ROBO1	“transcriptional regulation”
NFIX	“up-regulates quantity”	EPHA4	“transcriptional regulation”
NFIX	“up-regulates quantity”	EPHA5	“transcriptional regulation”
NFIX	“up-regulates quantity”	EPHA8	“transcriptional regulation”
NFIX	“up-regulates quantity”	RBFOX3	“transcriptional regulation”
MiR-744-5p	“down-regulates quantity by destabilization”	NFIX	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	49.8×	4e-07
somatic stem cell population maintenance	5	35.4×	2e-05
transforming growth factor beta receptor signaling pathway	5	22.7×	2e-04
transcription by RNA polymerase II	7	14.1×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	116
Likely pathogenic	52
Uncertain significance	128
Likely benign	155
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071849	NM_001365902.3(NFIX):c.120C>G (p.Tyr40Ter)	Pathogenic
1098319	NM_001365902.3(NFIX):c.148A>T (p.Lys50Ter)	Pathogenic
1175940	NM_001365902.3(NFIX):c.394G>T (p.Val132Phe)	Pathogenic
1319912	NM_001365902.3(NFIX):c.697+2T>G	Pathogenic
1334427	NM_001365902.3(NFIX):c.935G>A (p.Trp312Ter)	Pathogenic
1338333	NM_001365902.3(NFIX):c.179del (p.Leu60fs)	Pathogenic
1342494	NM_001365902.3(NFIX):c.586C>T (p.Gln196Ter)	Pathogenic
1410036	NC_000019.9:g.(?13186329)(13189569_?)del	Pathogenic
1453603	NM_001365902.3(NFIX):c.149_155dup (p.Glu53fs)	Pathogenic
1457731	NM_001365902.3(NFIX):c.1073_1076del (p.Arg358fs)	Pathogenic
1675170	NM_001365902.3(NFIX):c.1249G>T (p.Gly417Ter)	Pathogenic
1685979	NM_001365902.3(NFIX):c.163del (p.Ala55fs)	Pathogenic
1694456	NM_001365902.3(NFIX):c.226_242del (p.Leu76fs)	Pathogenic
1698906	NM_001365902.3(NFIX):c.765_766del (p.Ile256fs)	Pathogenic
1700444	NM_001365902.3(NFIX):c.1012C>T (p.Gln338Ter)	Pathogenic
1708174	NM_001365902.3(NFIX):c.146_153dup (p.Glu52fs)	Pathogenic
1710170	NM_001365902.3(NFIX):c.339_340dup (p.Ile114fs)	Pathogenic
1710192	NM_001365902.3(NFIX):c.31_47dup (p.Ile16fs)	Pathogenic
1806657	NM_001365902.3(NFIX):c.49G>T (p.Glu17Ter)	Pathogenic
2025950	NM_001365902.3(NFIX):c.1059del (p.Ala355fs)	Pathogenic
2068227	NM_001365902.3(NFIX):c.687_688dup (p.Val230fs)	Pathogenic
209174	NM_001365902.3(NFIX):c.338_342dup (p.Arg116fs)	Pathogenic
211591	NM_001365902.3(NFIX):c.1080_1096del (p.Ser361fs)	Pathogenic
211593	NM_001365902.3(NFIX):c.970_971del (p.Lys324fs)	Pathogenic
2138253	NM_001365902.3(NFIX):c.463C>T (p.Gln155Ter)	Pathogenic
2152310	NM_001365902.3(NFIX):c.559G>T (p.Glu187Ter)	Pathogenic
2412678	NM_001365902.3(NFIX):c.413del (p.Lys138fs)	Pathogenic
2441761	NM_001365902.3(NFIX):c.1090dup (p.Ala364fs)	Pathogenic
2499564	NM_001365902.3(NFIX):c.236T>C (p.Leu79Pro)	Pathogenic
2575650	NM_001365902.3(NFIX):c.347G>C (p.Arg116Pro)	Pathogenic

SpliceAI

3070 predictions. Top by Δscore:

Variant	Effect	Δscore
19:12995836:C:G	donor_gain	1.0000
19:13073035:T:TA	acceptor_gain	1.0000
19:13073042:TGCAG:T	acceptor_loss	1.0000
19:13073043:GCAGA:G	acceptor_loss	1.0000
19:13073045:A:AG	acceptor_gain	1.0000
19:13073046:G:GA	acceptor_gain	1.0000
19:13073046:GA:G	acceptor_gain	1.0000
19:13073108:CGGTC:C	donor_loss	1.0000
19:13073110:G:GG	donor_gain	1.0000
19:13073418:TCA:T	acceptor_loss	1.0000
19:13073420:A:AG	acceptor_gain	1.0000
19:13073420:A:G	acceptor_loss	1.0000
19:13073420:AG:A	acceptor_gain	1.0000
19:13073421:G:GG	acceptor_gain	1.0000
19:13073421:GG:G	acceptor_gain	1.0000
19:13073421:GGGCA:G	acceptor_gain	1.0000
19:13073493:CAGA:C	donor_gain	1.0000
19:13073494:AGA:A	donor_gain	1.0000
19:13073494:AGAG:A	donor_loss	1.0000
19:13073495:GA:G	donor_gain	1.0000
19:13073495:GAG:G	donor_gain	1.0000
19:13073496:AG:A	donor_loss	1.0000
19:13073497:G:GG	donor_gain	1.0000
19:13073501:G:GG	donor_gain	1.0000
19:13073904:A:AG	acceptor_gain	1.0000
19:13073904:A:G	acceptor_loss	1.0000
19:13073905:G:GA	acceptor_gain	1.0000
19:13073905:GC:G	acceptor_gain	1.0000
19:13073905:GCT:G	acceptor_gain	1.0000
19:13073905:GCTC:G	acceptor_gain	1.0000

AlphaMissense

3250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:13025027:T:C	F12L	1.000
19:13025029:C:A	F12L	1.000
19:13025029:C:G	F12L	1.000
19:13025036:T:C	F15L	1.000
19:13025037:T:C	F15S	1.000
19:13025037:T:G	F15C	1.000
19:13025038:C:A	F15L	1.000
19:13025038:C:G	F15L	1.000
19:13025040:T:A	I16N	1.000
19:13025049:T:C	L19P	1.000
19:13025052:T:C	L20P	1.000
19:13025061:T:A	V23D	1.000
19:13025075:T:G	Y28D	1.000
19:13025081:T:A	W30R	1.000
19:13025081:T:C	W30R	1.000
19:13025083:G:C	W30C	1.000
19:13025083:G:T	W30C	1.000
19:13025084:T:C	F31L	1.000
19:13025085:T:C	F31S	1.000
19:13025085:T:G	F31C	1.000
19:13025086:C:A	F31L	1.000
19:13025086:C:G	F31L	1.000
19:13025089:C:A	N32K	1.000
19:13025089:C:G	N32K	1.000
19:13025091:T:C	L33P	1.000
19:13025095:G:C	Q34H	1.000
19:13025095:G:T	Q34H	1.000
19:13025100:G:C	R36P	1.000
19:13025102:A:G	K37E	1.000
19:13025104:G:C	K37N	1.000

dbSNP variants (sampled 300 via entrez): RS1000008991 (19:13026236 T>C), RS1000094569 (19:13053993 G>A), RS1000096751 (19:13049501 A>T), RS1000108592 (19:13074305 A>T), RS1000119571 (19:13062238 G>A,C), RS1000138926 (19:13019317 A>G), RS1000139785 (19:13073952 G>A), RS1000149885 (19:13088542 T>C), RS1000156911 (19:13067137 C>A,G), RS1000174161 (19:13018551 C>T), RS1000181775 (19:13036613 T>C), RS1000193497 (19:13061987 C>G), RS1000301387 (19:13012553 C>T), RS1000352077 (19:13012267 G>C,T), RS1000371877 (19:13096273 T>C)

Disease associations

OMIM: gene MIM:164005 | disease phenotypes: MIM:602535, MIM:614753, MIM:150280, MIM:249300

GenCC curated gene-disease

Disease	Classification	Inheritance
Marshall-Smith syndrome	Definitive	Autosomal dominant
Malan overgrowth syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Marshall-Smith syndrome	Definitive	AD
Malan overgrowth syndrome	Definitive	AD

Mondo (8): Marshall-Smith syndrome (MONDO:0011244), Malan overgrowth syndrome (MONDO:0013885), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), strabismus (MONDO:0003432), exophthalmos (MONDO:0004770), congenital laryngomalacia (MONDO:0007878), megalocornea (MONDO:0009576)

Orphanet (4): Malan overgrowth syndrome (Orphanet:420179), Marshall-Smith syndrome (Orphanet:561), Congenital laryngomalacia (Orphanet:2373), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

202 total (30 of 202 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000098	Tall stature
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000300	Oval face
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000340	Sloping forehead
HP:0000347	Micrognathia

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000387_1	Bipolar disorder	2.000000e-07
GCST001647_1	Bipolar disorder	2.000000e-07
GCST001647_14	Bipolar disorder	3.000000e-07
GCST001647_2	Bipolar disorder	2.000000e-07
GCST001647_3	Bipolar disorder	4.000000e-07
GCST001647_4	Bipolar disorder	4.000000e-07
GCST002595_9	Clozapine-induced agranulocytosis	1.000000e-06
GCST002783_574	Body mass index	2.000000e-06
GCST004139_6	Bipolar disorder	6.000000e-10
GCST004608_132	Granulocyte percentage of myeloid white cells	2.000000e-10
GCST004609_94	Monocyte percentage of white cells	2.000000e-09
GCST004625_209	Monocyte count	4.000000e-09
GCST005316_233	Intelligence (MTAG)	2.000000e-09
GCST005316_234	Intelligence (MTAG)	2.000000e-08
GCST006979_742	Heel bone mineral density	4.000000e-15
GCST010002_148	Refractive error	2.000000e-11
GCST010703_320	Brain morphology (MOSTest)	2.000000e-21
GCST011616_29	Cortical volume	3.000000e-11
GCST011617_18	Cortical surface area	3.000000e-26
GCST90002384_446	Hemoglobin	3.000000e-09
GCST90002388_39	Lymphocyte count	4.000000e-16
GCST90002390_529	Mean corpuscular hemoglobin	2.000000e-11
GCST90002392_67	Mean corpuscular volume	2.000000e-12
GCST90002392_68	Mean corpuscular volume	1.000000e-15
GCST90002393_644	Monocyte count	1.000000e-12
GCST90002394_441	Monocyte percentage of white cells	3.000000e-17
GCST90002394_442	Monocyte percentage of white cells	8.000000e-19
GCST90002396_21	Mean reticulocyte volume	2.000000e-10
GCST90002400_270	Plateletcrit	5.000000e-16
GCST90020026_93	Hip index	1.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004337	intelligence
EFO:0009270	heel bone mineral density
EFO:0004346	neuroimaging measurement
EFO:0004509	hemoglobin measurement
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D005094	Exophthalmos	C11.675.349
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D055092	Laryngomalacia	C05.182.310; C08.360.563; C09.400.563; C16.131.621.568; C17.300.182.310
D065886	Neurodevelopmental Disorders	F03.625
D013285	Strabismus	C10.292.562.887; C11.590.810
C536026	Marshall-Smith syndrome (supp.)
C562829	Megalocornea (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

68 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression	4
Cisplatin	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	increases expression, decreases expression, increases abundance, affects cotreatment	2
GSK-J4	increases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	increases methylation, affects cotreatment	1
lead acetate	affects cotreatment, increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	affects expression	1
beta-lapachone	decreases expression	1
chromous chloride	affects cotreatment, increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects expression	1
chromic oxide	affects cotreatment, increases expression	1
manganese chloride	decreases expression	1
benzo(e)pyrene	affects methylation	1
4-hydroxy-2-nonenal	decreases expression	1
2,2’,3’,4,4’,5-hexachlorobiphenyl	affects expression	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
PCB 180	affects expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	increases expression	1
Temozolomide	affects response to substance	1
Decitabine	affects reaction, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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,
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
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
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
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
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
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
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)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays