GDF6

Summary

GDF6 (growth differentiation factor 6, HGNC:4221) is a protein-coding gene on chromosome 8q22.1, encoding Growth/differentiation factor 6 (Q6KF10). Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis.

Source: NCBI Gene 392255 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microphthalmia (Definitive, GenCC) — +6 more curated relationships
• Clinical variants (ClinVar): 501 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 91
• MANE Select transcript: NM_001001557

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4221
Approved symbol	GDF6
Name	growth differentiation factor 6
Location	8q22.1
Locus type	gene with protein product
Status	Approved
Aliases	BMP13, KFS, KFS1
Ensembl gene	ENSG00000156466
Ensembl biotype	protein_coding
OMIM	601147
Entrez	392255

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000287020

RefSeq mRNA: 1 — MANE Select: NM_001001557 NM_001001557

CCDS: CCDS34926

Canonical transcript exons

ENST00000287020 — 2 exons

Exon	Start	End
ENSE00001026677	96160287	96160806
ENSE00001156799	96142333	96145524

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 77.12.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3388 / max 181.7860, expressed in 373 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94017	1.3388	373

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	77.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.83	gold quality
ventricular zone	UBERON:0003053	68.29	gold quality
gall bladder	UBERON:0002110	67.97	gold quality
right atrium auricular region	UBERON:0006631	67.38	gold quality
mucosa of stomach	UBERON:0001199	65.77	gold quality
right coronary artery	UBERON:0001625	64.83	gold quality
calcaneal tendon	UBERON:0003701	63.74	gold quality
smooth muscle tissue	UBERON:0001135	62.63	gold quality
left coronary artery	UBERON:0001626	60.94	gold quality
ascending aorta	UBERON:0001496	60.40	gold quality
omental fat pad	UBERON:0010414	60.34	gold quality
colonic epithelium	UBERON:0000397	59.95	gold quality
thoracic aorta	UBERON:0001515	59.65	gold quality
myometrium	UBERON:0001296	59.47	gold quality
vermiform appendix	UBERON:0001154	59.12	gold quality
heart	UBERON:0000948	57.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	56.60	gold quality
lower esophagus	UBERON:0013473	56.48	gold quality
body of uterus	UBERON:0009853	56.39	gold quality
urinary bladder	UBERON:0001255	56.23	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	56.20	gold quality
sural nerve	UBERON:0015488	54.76	gold quality
islet of Langerhans	UBERON:0000006	54.60	gold quality
tibial artery	UBERON:0007610	54.23	gold quality
muscle layer of sigmoid colon	UBERON:0035805	54.23	gold quality
fundus of stomach	UBERON:0001160	54.21	gold quality
popliteal artery	UBERON:0002250	54.20	gold quality
adipose tissue	UBERON:0001013	53.99	gold quality
left uterine tube	UBERON:0001303	53.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting GDF6, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862

Literature-anchored findings (GeneRIF, showing 25)

• The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrate the key role of GDF6 in ocular development. (PMID:17236135)
• Mutation screening of a large and clinically diverse Klippel-Feil syndrome (KFS) cohort has identified GDF6 missense mutations in both familial and sporadic KFS patients. (PMID:18425797)
• These data establish the important role of growth differentiation factor 6 in ocular and vertebral development. (PMID:19129173)
• BMP-13 inhibited osteogenic differentiation of bone marrow multipotent mesenchymal stromal cells, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation (PMID:19240811)
• These data suggest a potential role for BMP-13 (the human homologue to GDF-6) in tendon matrix modeling and/or remodeling. (PMID:19492402)
• induces ligamentogenic differentiation in mesenchymal progenitors (PMID:20334610)
• studies show that even though tenogenic (BMP 12 and BMP 13) and osteogenic (BMP2) BMPs bind the same receptors with high affinity they signal much differently and result in differential activation of osteogenic and tenogenic markers (PMID:21702718)
• a critical role of HTRA1 in the regulation of angiogenesis via TGF-beta signaling and identified GDF6 as a novel disease gene for AMD. (PMID:22049084)
• Deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. (PMID:23307924)
• GDF6 is overexpressed in Leri’s pleonosteosis. (PMID:24442880)
• There was a possible weak association between the rs6982567 near GDF6 and polypoidal choroidal vasculopathy in this replication study with an independent Han Chinese cohort. (PMID:25416513)
• BMP13 has a role in enhancing extracellular matrix accumulation and inducing cell migration in certain intervertebral disc cells (PMID:26134557)
• As fetal age increased, the expression of growth differentiation factor 6 was decreased correspondingly with the progress of ossification in vertebral bodies and restricted to cartilaginous regions. (PMID:26184900)
• findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with Multiple Synostoses Syndrome 4. (PMID:26643732)
• GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. (PMID:29284606)
• miR-98 is involved in missed abortion by targeting GDF6 and FAPP2. (PMID:32045359)
• Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development. (PMID:32369452)
• Rare heterozygous GDF6 variants in patients with renal anomalies. (PMID:32737436)
• Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation. (PMID:32992671)
• GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth. (PMID:33147457)
• A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression. (PMID:34319658)
• siRNA Mediate RNA Interference Concordant with Early On-Target Transient Transcriptional Interference. (PMID:34440463)
• GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment. (PMID:34573339)
• Bone morphogenetic protein 13 in hepatic stellate cells and hepatic fibrosis. (PMID:35442524)
• A novel DNA methylation signature revealed GDF6 and RCC1 as potential prognostic biomarkers correlated with cell proliferation in clear cell renal cell carcinoma. (PMID:38087057)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gdf6	ENSMUSG00000051279
rattus_norvegicus	Gdf6	ENSRNOG00000067800

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 6 — Q6KF10 (reviewed: Q6KF10)

Alternative names: Bone morphogenetic protein 13, Growth/differentiation factor 16

All UniProt accessions (2): Q6KF10, A0A0S2A5D6

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. Plays a key role in regulating apoptosis during retinal development. Establishes dorsal-ventral positional information in the retina and controls the formation of the retinotectal map. Required for normal formation of bones and joints in the limbs, skull, digits and axial skeleton. Plays a key role in establishing boundaries between skeletal elements during development. Regulation of GDF6 expression seems to be a mechanism for evolving species-specific changes in skeletal structures. Seems to positively regulate differentiation of chondrogenic tissue through the growth factor receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is inhibited by NOG. Also involved in the induction of adipogenesis from mesenchymal stem cells. This mechanism acts through the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Secreted.

Disease relevance. Klippel-Feil syndrome 1, autosomal dominant (KFS1) [MIM:118100] A skeletal disorder characterized by congenital fusion of cervical vertebrae. It is due to a failure in the normal segmentation of vertebrae during the early weeks of fetal development. The clinical triad consists of short neck, low posterior hairline, and limited neck movement. Deafness is a feature in some cases and may be of sensorineural, conductive, or mixed type. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving GDF6 has been found in a patient with Klippel-Feil syndrome (KFS). Paracentric inv(8)(q22;2q23.3). Microphthalmia, isolated, 4 (MCOP4) [MIM:613094] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. The disease is caused by variants affecting the gene represented in this entry. Leber congenital amaurosis 17 (LCA17) [MIM:615360] A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or almost absent pupillary responses, photophobia, high hyperopia and keratoconus. The disease is caused by variants affecting the gene represented in this entry. Multiple synostoses syndrome 4 (SYNS4) [MIM:617898] A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. SYNS4 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 118, with cochlear aplasia (DFNB118) [MIM:619553] A form of non-syndromic deafness characterized by congenital profound sensorineural hearing loss and cochlear aplasia. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The gene represented in this entry is involved in disease pathogenesis. Homozygous deletions on chromosome 8 removing putative enhancers of GDF6, segregate with the disease in families with congenital deafness and cochlear aplasia.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_001001557* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001111	TGF-b_propeptide	Domain
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF00688

UniProt features (29 total): sequence variant 14, disulfide bond 4, region of interest 3, compositionally biased region 3, signal peptide 1, propeptide 1, chain 1, sequence conflict 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6KF10-F1	70.88	0.35

Functional residue map

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

Disulfide bonds (4): 354–420, 383–452, 387–454, 419

Glycosylation sites (1): 114

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 319 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, BENPORATH_ES_WITH_H3K27ME3, GOBP_METANEPHROS_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GTCTACC_MIR379, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, AATGGAG_MIR136, AAACCAC_MIR140, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (14): metanephros development (GO:0001656), apoptotic process (GO:0006915), epithelial cell migration (GO:0010631), BMP signaling pathway (GO:0030509), positive regulation of chondrocyte differentiation (GO:0032332), activin receptor signaling pathway (GO:0032924), cell migration involved in metanephros development (GO:0035788), fat cell differentiation (GO:0045444), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of SMAD protein signal transduction (GO:0060391), positive regulation of p38MAPK cascade (GO:1900745), retinal cell apoptotic process (GO:1990009), positive regulation of cell differentiation (GO:0045597)

GO Molecular Function (3): cytokine activity (GO:0005125), growth factor activity (GO:0008083), identical protein binding (GO:0042802)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transforming growth factor beta receptor superfamily signaling pathway	2
positive regulation of cell differentiation	2
cell differentiation	2
receptor ligand activity	2
kidney development	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
ameboidal-type cell migration	1
epithelium migration	1
cellular response to BMP stimulus	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
positive regulation of cartilage development	1
metanephros development	1
cell migration involved in kidney development	1
neuron differentiation	1
regulation of neuron differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of intracellular signal transduction	1
p38MAPK cascade	1
positive regulation of MAPK cascade	1
regulation of p38MAPK cascade	1
apoptotic process	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
protein binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDF6	PAEP	P09466	842
GDF6	BMPR1B	P78366	771
GDF6	NOG	Q13253	745
GDF6	BMPR1A	P36894	704
GDF6	VSX2	P58304	647
GDF6	CSMD3	Q7Z407	638
GDF6	BMPR2	Q13873	615
GDF6	ACVR2A	P27037	593
GDF6	ACVR2B	Q13705	588
GDF6	ACVR1B	P36896	555
GDF6	TNMD	Q9H2S6	533
GDF6	ACVR1C	Q8NER5	508
GDF6	WNT11	O96014	504
GDF6	ACAN	P16112	499
GDF6	STRA6	Q9BX79	489

IntAct

1 interactions, top by confidence:

BioGRID (4): GDF6 (Affinity Capture-MS), BMPR1B (Reconstituted Complex), BMPR2 (Reconstituted Complex), BMPR1A (Reconstituted Complex)

ESM2 similar proteins: A1L0T3, A1L4H1, A6QNY1, D3YZF7, O95428, P28698, P30203, P55068, P55106, P59222, P98162, Q04756, Q14767, Q28019, Q28062, Q28256, Q28343, Q28670, Q3U515, Q4G0T1, Q5F378, Q5HZW5, Q61003, Q61361, Q6H9L7, Q6KF10, Q6PGE4, Q6QNF4, Q7TQH7, Q7Z4F1, Q86T13, Q86VR7, Q86VZ4, Q8BV57, Q8BZE1, Q8CB67, Q8VCP9, Q8WTU2, Q91V98, Q96DN2

Diamond homologs: A1C2U3, A1C2U6, A1C2U7, A1C2V0, A1C2V5, A8E7N9, G5EEL5, O08689, O14793, O18828, O18830, O18831, O18836, O35312, O42220, O42221, O42222, O46576, O61643, O95390, O95393, P09534, P12644, P12645, P17491, P18075, P20722, P20863, P22003, P22004, P22444, P23359, P27091, P27539, P35621, P43026, P43027, P43028, P43029, P48970

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GDF6	up-regulates	BMPR1A	binding
GDF6	up-regulates	BMPR2	binding
GDF6	up-regulates	BMPR1A/1B/2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	268
Likely benign	155
Benign	40

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2506527	GRCh37/hg19 8q21.3-22.1(chr8:89179899-97978274)	Pathogenic
495116	NM_001001557.4(GDF6):c.1330T>A (p.Tyr444Asn)	Pathogenic
60533	NM_001001557.4(GDF6):c.876G>Y (p.Glu292Asp)	Pathogenic
1679350	NM_001001557.4(GDF6):c.986_1005del (p.Pro329fs)	Likely pathogenic
235732	NM_001001557.4(GDF6):c.73C>T (p.Gln25Ter)	Likely pathogenic
4526793	NM_001001557.4(GDF6):c.1318_1320del (p.Val440del)	Likely pathogenic

SpliceAI

365 predictions. Top by Δscore:

Variant	Effect	Δscore
8:96145522:CGT:C	acceptor_gain	1.0000
8:96145521:TCGT:T	acceptor_gain	0.9900
8:96145522:CGTC:C	acceptor_gain	0.9900
8:96145524:TC:T	acceptor_loss	0.9900
8:96145525:C:A	acceptor_loss	0.9900
8:96145525:C:CC	acceptor_gain	0.9900
8:96145526:T:C	acceptor_loss	0.9900
8:96160280:CACTT:C	donor_loss	0.9900
8:96160281:ACTTA:A	donor_loss	0.9900
8:96160282:CTTAC:C	donor_loss	0.9900
8:96160283:TTAC:T	donor_loss	0.9900
8:96160284:TACC:T	donor_loss	0.9900
8:96160285:A:C	donor_loss	0.9900
8:96160286:C:CT	donor_loss	0.9900
8:96145520:ATCGT:A	acceptor_gain	0.9800
8:96145523:GT:G	acceptor_gain	0.9800
8:96160279:CCACT:C	donor_loss	0.9800
8:96160289:AGTCC:A	donor_gain	0.9800
8:96160285:A:AC	donor_gain	0.9600
8:96160286:C:CC	donor_gain	0.9600
8:96145529:G:T	acceptor_gain	0.9300
8:96145528:C:CT	acceptor_gain	0.9200
8:96160289:AGTC:A	donor_gain	0.9200
8:96160475:T:TA	donor_gain	0.9200
8:96145532:A:C	acceptor_gain	0.9100
8:96147121:C:CT	donor_gain	0.8800
8:96147122:T:TT	donor_gain	0.8800
8:96158660:T:TC	acceptor_gain	0.8800
8:96146396:CTAGT:C	donor_gain	0.8500
8:96145532:A:AC	acceptor_gain	0.8400

AlphaMissense

2916 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:96144639:A:G	L431P	1.000
8:96144672:C:T	C420Y	1.000
8:96144714:A:G	L406P	1.000
8:96144765:A:C	F389C	1.000
8:96144771:C:T	C387Y	1.000
8:96144782:G:C	C383W	1.000
8:96144783:C:G	C383S	1.000
8:96144783:C:T	C383Y	1.000
8:96144784:A:T	C383S	1.000
8:96144818:C:A	W371C	1.000
8:96144818:C:G	W371C	1.000
8:96144827:C:A	W368C	1.000
8:96144827:C:G	W368C	1.000
8:96144829:A:G	W368R	1.000
8:96144829:A:T	W368R	1.000
8:96144842:G:C	F363L	1.000
8:96144842:G:T	F363L	1.000
8:96144843:A:C	F363C	1.000
8:96144843:A:G	F363S	1.000
8:96144844:A:G	F363L	1.000
8:96144570:C:G	C454S	0.999
8:96144571:A:G	C454R	0.999
8:96144571:A:T	C454S	0.999
8:96144575:G:C	C452W	0.999
8:96144576:C:T	C452Y	0.999
8:96144590:C:A	M447I	0.999
8:96144590:C:G	M447I	0.999
8:96144590:C:T	M447I	0.999
8:96144610:A:C	Y441D	0.999
8:96144642:A:T	I430N	0.999

dbSNP variants (sampled 300 via entrez): RS1000078672 (8:96161928 C>G,T), RS1000496892 (8:96146727 TAGAG>T,TAGAGAG), RS1000609489 (8:96147033 C>T), RS1000674516 (8:96151127 T>C), RS1000715391 (8:96146439 G>T), RS1000814299 (8:96144326 T>C), RS1000854720 (8:96158712 C>T), RS1001018448 (8:96157464 G>T), RS1001106127 (8:96153010 C>G,T), RS1001461195 (8:96150716 T>G), RS1001648656 (8:96144184 C>T), RS1001909971 (8:96162649 C>A,T), RS1002044234 (8:96147119 C>G), RS1002147232 (8:96147301 T>C), RS1002321333 (8:96153648 G>C)

Disease associations

OMIM: gene MIM:601147 | disease phenotypes: MIM:118100, MIM:613094, MIM:613703, MIM:615360, MIM:617898, MIM:610805, MIM:607060

GenCC curated gene-disease

Disease	Classification	Inheritance
Klippel-Feil syndrome 1, autosomal dominant	Definitive	Autosomal dominant
microphthalmia	Definitive	Autosomal dominant
multiple synostoses syndrome 4	Strong	Autosomal dominant
isolated Klippel-Feil syndrome	Supportive	Autosomal dominant
Leber congenital amaurosis	Supportive	Autosomal dominant
isolated microphthalmia 4	Limited	Autosomal dominant
Leber congenital amaurosis 17	Limited	Unknown

Mondo (11): Klippel-Feil syndrome 1, autosomal dominant (MONDO:0007306), isolated microphthalmia 4 (MONDO:0013130), microphthalmia, isolated, with coloboma 6 (MONDO:0013376), Leber congenital amaurosis 17 (MONDO:0014145), multiple synostoses syndrome 4 (MONDO:0054752), inherited retinal dystrophy (MONDO:0019118), congenital anomaly of kidney and urinary tract (MONDO:0019719), autosomal dominant Parkinson disease 8 (MONDO:0011764), (MONDO:0016520), Leber congenital amaurosis (MONDO:0018998), microphthalmia (MONDO:0021129)

Orphanet (7): Isolated Klippel-Feil syndrome (Orphanet:2345), Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Leber congenital amaurosis (Orphanet:65), Colobomatous microphthalmia (Orphanet:98938), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Renal or urinary tract malformation (Orphanet:93545), Hereditary late-onset Parkinson disease (Orphanet:411602)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000086	Ectopic kidney
HP:0000119	Abnormality of the genitourinary system
HP:0000122	Unilateral renal agenesis
HP:0000175	Cleft palate
HP:0000324	Facial asymmetry
HP:0000362	Otosclerosis
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000465	Webbed neck
HP:0000466	Limited neck range of motion
HP:0000470	Short neck
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000563	Keratoconus
HP:0000568	Microphthalmia
HP:0000589	Coloboma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000707	Abnormality of the nervous system
HP:0000729	Autistic behavior
HP:0000772	Abnormal rib morphology
HP:0000912	Sprengel anomaly

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D008850	Microphthalmos	C11.250.566; C16.131.384.666
D058499	Retinal Dystrophies	C11.768.585.658
C566906	Cakut (supp.)
C536887	Klippel Feil syndrome dominant type (supp.)
C567757	Microphthalmia, Isolated 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
ethyl-p-hydroxybenzoate	increases expression	1
2-butenal	decreases expression	1
arsenite	increases methylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
3-nitrobenzanthrone	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	increases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cannabinoids	affects methylation, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	increases expression	1
Estradiol	increases expression, affects cotreatment	1
Indomethacin	increases expression	1
Oxygen	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Tetrachlorodibenzodioxin	affects expression	1
Triclosan	decreases expression	1
Tunicamycin	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT03741790	Not specified	ACTIVE_NOT_RECRUITING	Airway Management of Pediatric Patients With Klippel-Feil Syndrome
NCT06489392	Not specified	COMPLETED	Mehri Turki Webbed Neck Classification
NCT03913143	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT00749957	PHASE1/PHASE2	COMPLETED	Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis
NCT01208389	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2
NCT01496040	PHASE1/PHASE2	COMPLETED	Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65
NCT02781480	PHASE1/PHASE2	COMPLETED	Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA)
NCT03913130	PHASE1/PHASE2	TERMINATED	Extension Study to Study PQ-110-001 (NCT03140969)
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT05203939	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis
NCT05906953	PHASE1/PHASE2	RECRUITING	Safety and Efficacy Trial of HG004 for Leber Congenital Amaurosis Related to Rpe65 Gene Mutations (STAR)
NCT06088992	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Leber Congenital Amaurosis Inherited Blindness of Gene Therapy Trial(LIGHT)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02575430	Not specified	COMPLETED	Natural History Study in Inherited Retinal Disease Subjects Caused by Mutations in RPE65 or LRAT
NCT02714816	Not specified	COMPLETED	Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
NCT02946879	Not specified	COMPLETED	Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65)
NCT02970266	Not specified	COMPLETED	Genetic Decryption of Leber Congenital Amaurosis (LCA) in a Large Cohort of Independent Families.
NCT07026565	Not specified	NOT_YET_RECRUITING	Psychotherapy Group for Parents of Children With LCA
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT03748732	Not specified	UNKNOWN	Extensive Circumferential Partial Thickness Sclerectomy in Nanophthalmic Eyes
NCT04759560	Not specified	UNKNOWN	Biometric Characteristics of the Eye With Microcornea/Microphthalmia and Congenital Cataract Before And After Cataract Extraction
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10