NDN

Summary

NDN (necdin, MAGE family member, HGNC:7675) is a protein-coding gene on chromosome 15q11.2, encoding Necdin (Q99608). Growth suppressor that facilitates the entry of the cell into cell cycle arrest.

This intronless gene is located in the Prader-Willi syndrome deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mouse suggest that the protein encoded by this gene may suppress growth in postmitotic neurons.

Source: NCBI Gene 4692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Prader-Willi syndrome (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 65 total
• Phenotypes (HPO): 75
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002487

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7675
Approved symbol	NDN
Name	necdin, MAGE family member
Location	15q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HsT16328, PWCR
Ensembl gene	ENSG00000182636
Ensembl biotype	protein_coding
OMIM	602117
Entrez	4692

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000649030

RefSeq mRNA: 1 — MANE Select: NM_002487 NM_002487

CCDS: CCDS10014

Canonical transcript exons

ENST00000649030 — 1 exons

Exon	Start	End
ENSE00003831752	23685400	23687305

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.0311 / max 218.0885, expressed in 1217 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148999	18.8715	1202
148998	2.4295	917
148997	1.7302	784

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.10	gold quality
adrenal tissue	UBERON:0018303	98.01	gold quality
tendon of biceps brachii	UBERON:0008188	97.99	gold quality
medial globus pallidus	UBERON:0002477	96.42	gold quality
endocervix	UBERON:0000458	96.03	gold quality
nucleus accumbens	UBERON:0001882	95.96	gold quality
cortical plate	UBERON:0005343	95.49	gold quality
right ovary	UBERON:0002118	95.42	gold quality
hypothalamus	UBERON:0001898	95.31	gold quality
left ovary	UBERON:0002119	95.29	gold quality
urethra	UBERON:0000057	95.28	gold quality
globus pallidus	UBERON:0001875	95.18	gold quality
ovary	UBERON:0000992	95.12	gold quality
parietal pleura	UBERON:0002400	94.93	gold quality
ganglionic eminence	UBERON:0004023	94.79	gold quality
pons	UBERON:0000988	94.72	gold quality
superior vestibular nucleus	UBERON:0007227	94.69	gold quality
left uterine tube	UBERON:0001303	94.58	gold quality
middle temporal gyrus	UBERON:0002771	94.49	gold quality
pituitary gland	UBERON:0000007	94.45	gold quality
body of uterus	UBERON:0009853	94.45	gold quality
prefrontal cortex	UBERON:0000451	94.43	gold quality
adenohypophysis	UBERON:0002196	94.31	gold quality
dorsal root ganglion	UBERON:0000044	94.27	gold quality
right adrenal gland cortex	UBERON:0035827	94.23	gold quality
right adrenal gland	UBERON:0001233	94.21	gold quality
ectocervix	UBERON:0012249	94.08	gold quality
embryo	UBERON:0000922	94.05	gold quality
adrenal cortex	UBERON:0001235	94.03	gold quality
left adrenal gland cortex	UBERON:0035825	94.03	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	240.16
E-MTAB-10287	yes	100.63
E-GEOD-134144	yes	33.06
E-ANND-3	yes	16.55
E-CURD-112	yes	5.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYC	Activation

Upstream regulators (CollecTRI, top): CREB1, FOXO1, NHLH1, NHLH2, STAT3, TAF1, TP53

miRNA regulators (miRDB)

56 targeting NDN, 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-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-5009-3P	99.45	69.43	1341

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 26)

• the constitutively up-regulated expression of pre-IL-1 alpha in the nuclei of systemic sclerosis (SSc) fibroblasts up-regulates proliferation and matrix production of SSC fibroblasts through binding necdin (PMID:12913118)
• Tissue-specific gene expression regulation and imprinted epigenetic modifications of the human NDN gene. (PMID:15247330)
• Necdin can be a novel negative regulator of HIF-1alpha stability via the direct interaction. (PMID:15978586)
• Lack of Necdin expression induces perinatal serotonergic alterations that affect the maturation and function of the respiratory network, inducing breathing deficits in mice and probably in Prader-Willi patients. (PMID:18272695)
• Data suggest that Nogo-A is a novel necdin binding protein and inhibits necdin-accelerated neuronal neurite outgrowth by sequestering necdin in the cytoplasm. (PMID:19386232)
• regulates neuronal development. (review) (PMID:19517793)
• Confirmation of NDN as a tumor suppressor may have implications for monitoring of PWS patients and could present a novel cancer therapeutic target (PMID:19626646)
• Necdin is a key protein regulating polarization of the cytoskeleton and myosin activation during development. (PMID:20665884)
• Data suggest that the effects of necdin deletion on the developing nervous system may depend on the relative expression of p75NTR and TrkA in the cells of particular regions of the nervous system. (PMID:21150695)
• rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in hypogonadism phenotype. (PMID:21543378)
• Necdin is implicated through the TNF-receptor 1 pathway in the developmental death of motoneuron (PMID:21912643)
• Necdin, a negative growth regulator,identified as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. (PMID:22046235)
• In pre-adipocytes, necdin over-expression inhibits adipogenesis, while reducing necdin levels enhances adipogenic differentiation in tissue culture cell (PMID:22305984)
• necdin has multiple roles within protein complexes in different subcellular compartments, and indicate that it can utilize multiple karyopherin-dependent pathways to modulate its localization. (PMID:22442722)
• Necdin expression declined during replicative aging of IMR90 primary human fibroblasts or after induction of premature senescence.Showed that in normal human cells, Necdin expression mimicked the effect of p53 inactivation by increasing radioresistance. (PMID:22691188)
• necdin exerts its pro-survival activity by counteracting the action of the pro-apoptotic protein Cell Cycle Apoptosis Regulatory Protein (CCAR1/CARP1) (PMID:22905258)
• Hypermethylation and mutation of necdin is associated with neoplasms. (PMID:23549060)
• Germline single nucleotide polymorphism in necdin gene is associated with breast cancer. (PMID:26384308)
• NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas (PMID:26518708)
• NDN is an imprinted tumor suppressor gene which affects cancer cell motility, invasion and growth and that its loss of function in ovarian cancer can be caused by both genetic and epigenetic mechanisms. (PMID:26689988)
• One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region (PMID:28213671)
• this study shows that hypermethylation of NDN promotes cell proliferation by activating the Wnt signaling pathway in colorectal cancer (PMID:28521288)
• the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia (PMID:29343559)
• We focused on three important regulatory DNA elements which are all differentially methylated regions (DMRs), methylated on the maternal allele: the PWS imprinting center (PWS-IC), which is a germline DMR and the somatic NDN and MKRN3 DMRs, hierarchically controlled by PWS-IC. (PMID:30102380)
• The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry. (PMID:32529326)
• The necdin gene is imprinted, with preferential expression from the paternal allele in human and mouse. (PMID:9302265)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndnl2	ENSDARG00000058212
mus_musculus	Ndn	ENSMUSG00000033585
rattus_norvegicus	Ndn	ENSRNOG00000010146
drosophila_melanogaster	MAGE	FBGN0037481

Paralogs (37): MAGEC2 (ENSG00000046774), TRO (ENSG00000067445), MAGEB2 (ENSG00000099399), MAGED2 (ENSG00000102316), MAGEB4 (ENSG00000120289), MAGEA9 (ENSG00000123584), MAGEA10 (ENSG00000124260), MAGEA4 (ENSG00000147381), MAGED4 (ENSG00000154545), MAGEC1 (ENSG00000155495), MAGEA8 (ENSG00000156009), MAGEC3 (ENSG00000165509), MAGEB6 (ENSG00000176746), MAGEB18 (ENSG00000176774), MAGEF1 (ENSG00000177383), MAGEB10 (ENSG00000177689), MAGED1 (ENSG00000179222), MAGEB17 (ENSG00000182798), MAGEA2B (ENSG00000183305), NSMCE3 (ENSG00000185115), MAGEA11 (ENSG00000185247), MAGEE2 (ENSG00000186675), MAGED4B (ENSG00000187243), MAGEH1 (ENSG00000187601), MAGEB5 (ENSG00000188408), MAGEB16 (ENSG00000189023), MAGEA6 (ENSG00000197172), MAGEA1 (ENSG00000198681), MAGEB3 (ENSG00000198798), MAGEE1 (ENSG00000198934), MAGEA12 (ENSG00000213401), MAGEB1 (ENSG00000214107), MAGEA3 (ENSG00000221867), MAGEB6B (ENSG00000232030), MAGEL2 (ENSG00000254585), MAGEA9B (ENSG00000267978), MAGEA2 (ENSG00000268606)

Protein

Protein identifiers

Necdin — Q99608 (reviewed: Q99608)

All UniProt accessions (2): Q99608, X5D982

UniProt curated annotations — full annotation on UniProt →

Function. Growth suppressor that facilitates the entry of the cell into cell cycle arrest. Functionally similar to the retinoblastoma protein it binds to and represses the activity of cell-cycle-promoting proteins such as SV40 large T antigen, adenovirus E1A, and the transcription factor E2F. Necdin also interacts with p53 and works in an additive manner to inhibit cell growth. Also functions as a transcription factor and directly binds to specific guanosine-rich DNA sequences.

Subunit / interactions. Binds to the transactivation domains of E2F1 and p53. Binds also SV40 large T antigen and adenovirus E1A. Interacts with nucleobindin 1 and 2.

Subcellular location. Perikaryon. Nucleus.

Tissue specificity. Almost ubiquitous. Detected in fetal brain, lung, liver and kidney; in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine and colon. Not detected in peripheral blood leukocytes. In brain, restricted to post-mitotic neurons.

Miscellaneous. Located in the Prader-Willi syndrome (PWS) chromosome region. Prader-Willi syndrome is a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene, the necdin gene, and possibly other genes within the chromosome region 15q11-q13.

RefSeq proteins (1): NP_002478* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002190	MHD_dom	Domain
IPR037445	MAGE	Family
IPR041898	MAGE_WH1	Homologous_superfamily
IPR041899	MAGE_WH2	Homologous_superfamily

Pfam: PF01454

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

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99608-F1	68.01	0.04

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-449147	Signaling by Interleukins

MSigDB gene sets: 381 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_NEURON_RECOGNITION, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, TSENG_IRS1_TARGETS_UP, GOBP_NEURON_PROJECTION_EXTENSION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, PAL_PRMT5_TARGETS_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GGGTGGRR_PAX4_03, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_70

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), neuron migration (GO:0001764), respiratory system process (GO:0003016), axonal fasciculation (GO:0007413), central nervous system development (GO:0007417), glial cell migration (GO:0008347), post-embryonic development (GO:0009791), sensory perception of pain (GO:0019233), positive regulation of transcription by RNA polymerase II (GO:0045944), neurotrophin TRK receptor signaling pathway (GO:0048011), axon extension (GO:0048675), multicellular organismal-level homeostasis (GO:0048871), genomic imprinting (GO:0071514), regulation of DNA-templated transcription (GO:0006355), axonogenesis (GO:0007409), respiratory gaseous exchange by respiratory system (GO:0007585), neuron differentiation (GO:0030182), neuron development (GO:0048666)

GO Molecular Function (4): DNA binding (GO:0003677), gamma-tubulin binding (GO:0043015), promoter-specific chromatin binding (GO:1990841), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), protein-containing complex (GO:0032991), cell projection (GO:0042995), perikaryon (GO:0043204), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Interleukins	1
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
multicellular organismal process	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cell migration	2
generation of neurons	2
axon development	2
negative regulation of DNA-templated transcription	1
system process	1
respiratory gaseous exchange by respiratory system	1
neuron recognition	1
neuron projection fasciculation	1
nervous system development	1
system development	1
gliogenesis	1
multicellular organism development	1
sensory perception	1
positive regulation of DNA-templated transcription	1
cell surface receptor protein tyrosine kinase signaling pathway	1
neurotrophin signaling pathway	1
axonogenesis	1
neuron projection extension	1
homeostatic process	1
germ cell development	1
epigenetic programming of gene expression	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
cell differentiation	1
neuron differentiation	1
cell development	1
nucleic acid binding	1
tubulin binding	1
chromatin binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
centriole	1

Protein interactions and networks

STRING

1650 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDN	TP53	P04637	980
NDN	SNRPN	P14648	939
NDN	E2F1	Q01094	937
NDN	MKRN3	Q13064	922
NDN	ATP10A	O60312	829
NDN	UBE3A	P78355	801
NDN	NGFR	P08138	798
NDN	PJA1	Q8NG27	789
NDN	NPAP1	Q9NZP6	772
NDN	SIRT1	Q96EB6	736
NDN	GABRB3	P28472	705
NDN	OXT	P01178	660
NDN	CSAG1	Q6PB30	632
NDN	PPP1R9A	Q9ULJ8	621
NDN	HNRNPU	Q00839	616

IntAct

90 interactions, top by confidence:

A	B	Type	Score
NDN	EID1	psi-mi:“MI:0915”(physical association)	0.690
EID1	NDN	psi-mi:“MI:0915”(physical association)	0.690
NDN	NEFL	psi-mi:“MI:0915”(physical association)	0.670
SYAP1	NDN	psi-mi:“MI:0915”(physical association)	0.600
GRN	NDN	psi-mi:“MI:0915”(physical association)	0.560
NDN	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
NEFL	NDN	psi-mi:“MI:0915”(physical association)	0.560
NDN	WFS1	psi-mi:“MI:0915”(physical association)	0.560
HTT	NDN	psi-mi:“MI:0915”(physical association)	0.560
NDN	CDR2	psi-mi:“MI:0915”(physical association)	0.550
NDN	TP53	psi-mi:“MI:0915”(physical association)	0.550
EGFR	NDN	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (450): NDN (Two-hybrid), E2F1 (Two-hybrid), NUBP1 (Two-hybrid), NDN (Affinity Capture-Western), PPARGC1A (Affinity Capture-Western), NDN (Reconstituted Complex), PPARGC1A (Reconstituted Complex), NDN (Two-hybrid), TP53 (Affinity Capture-Western), NDN (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), NDN (Reconstituted Complex), NDN (Two-hybrid), NDN (Two-hybrid), MAGEL2 (Proximity Label-MS)

ESM2 similar proteins: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A8MXT2, B2KFW1, O15479, O15480, O15481, O15553, P0C6Y7, P10073, P17040, P25233, P43355, P43356, P43357, P43358, P43360, P43362, P43363, P43364, P43366, Q13342, Q16666, Q4R998, Q5PPP4, Q5RD14, Q6AY37, Q6PCZ4, Q8BQR7, Q8IWY8, Q8IX06, Q8N660, Q8N7X4, Q8TD90, Q96DU7, Q96LZ2, Q96M61, Q99608

Diamond homologs: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A6NCF6, A6QLI5, A8MXT2, O15479, O15480, O15481, O60732, P25233, P43355, P43356, P43357, P43358, P43360, P43361, P43362, P43363, P43364, P43365, P43366, Q12816, Q4R998, Q5PPP4, Q5RFC2, Q6AY37, Q6ITT4, Q6PCZ4, Q8BQR7, Q8N7X4, Q8TD90, Q8TD91, Q96JG8, Q96LZ2, Q96M61, Q96MG7, Q99608, Q9BE18

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
NDN	up-regulates	CDKN2A
NDN	down-regulates	BMI1
BMI1	down-regulates	NDN
NDN	“down-regulates quantity by destabilization”	PIAS1	binding
GNAO1	“up-regulates activity”	NDN
NDN	“up-regulates quantity by stabilization”	PPARGC1A	binding
NDN	“up-regulates activity”	EID1	binding
NDN	“up-regulates quantity by expression”	MYC	“transcriptional regulation”
NDN	“down-regulates activity”	E2F1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	10
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

38 predictions. Top by Δscore:

Variant	Effect	Δscore
15:23685929:CCA:C	acceptor_gain	0.9700
15:23685931:A:C	acceptor_gain	0.9400
15:23685930:CA:C	acceptor_gain	0.9300
15:23685930:C:T	acceptor_gain	0.9100
15:23685928:CCCA:C	acceptor_gain	0.8700
15:23685933:A:C	acceptor_gain	0.8100
15:23685931:A:AC	acceptor_gain	0.7000
15:23687203:A:AC	donor_gain	0.7000
15:23687204:C:CC	donor_gain	0.7000
15:23687199:C:A	donor_gain	0.5700
15:23687205:T:C	donor_gain	0.5400
15:23687063:G:GT	acceptor_gain	0.5200
15:23687195:AGAT:A	donor_gain	0.4000
15:23686389:C:CA	donor_gain	0.3900
15:23685902:AGTCT:A	acceptor_gain	0.3400
15:23686482:T:TA	donor_gain	0.3100
15:23686584:T:A	donor_gain	0.3000
15:23685933:A:AC	acceptor_gain	0.2900
15:23686506:C:CA	donor_gain	0.2900
15:23686616:T:TG	acceptor_gain	0.2900
15:23687195:AGATC:A	donor_gain	0.2700
15:23686503:A:AC	donor_gain	0.2600
15:23686504:C:CC	donor_gain	0.2600
15:23686617:T:G	acceptor_gain	0.2600
15:23686368:TAAAG:T	donor_gain	0.2500
15:23686369:AAAGA:A	donor_gain	0.2500
15:23686639:C:CT	acceptor_gain	0.2500
15:23686503:ACT:A	donor_gain	0.2200
15:23686504:CTC:C	donor_gain	0.2200
15:23686529:T:TA	donor_gain	0.2200

AlphaMissense

2100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:23686765:G:C	F151L	1.000
15:23686765:G:T	F151L	1.000
15:23686767:A:G	F151L	1.000
15:23686348:C:A	W290C	0.999
15:23686348:C:G	W290C	0.999
15:23686350:A:G	W290R	0.999
15:23686350:A:T	W290R	0.999
15:23686384:G:C	F278L	0.999
15:23686384:G:T	F278L	0.999
15:23686386:A:G	F278L	0.999
15:23686431:C:G	G263R	0.999
15:23686434:A:G	W262R	0.999
15:23686434:A:T	W262R	0.999
15:23686439:A:G	F260S	0.999
15:23686484:A:G	L245P	0.999
15:23686534:G:C	F228L	0.999
15:23686534:G:T	F228L	0.999
15:23686536:A:G	F228L	0.999
15:23686587:A:G	W211R	0.999
15:23686587:A:T	W211R	0.999
15:23686630:G:C	S196R	0.999
15:23686630:G:T	S196R	0.999
15:23686632:T:G	S196R	0.999
15:23686724:A:G	F165S	0.999
15:23686767:A:T	F151I	0.999
15:23686369:A:C	F283L	0.998
15:23686369:A:T	F283L	0.998
15:23686371:A:G	F283L	0.998
15:23686430:C:A	G263V	0.998
15:23686432:C:A	W262C	0.998

dbSNP variants (sampled 300 via entrez): RS1000195044 (15:23687662 A>G), RS1000369005 (15:23687315 C>A,G,T), RS1000864017 (15:23685568 T>C), RS1001630455 (15:23685028 C>A), RS1003275475 (15:23685296 C>T), RS1004375696 (15:23687763 G>C), RS1004423179 (15:23688060 C>T), RS1005917965 (15:23686651 G>A), RS1007881451 (15:23689250 T>C), RS1012136328 (15:23685625 C>T), RS1013125967 (15:23687294 G>A,C), RS1013289231 (15:23688518 C>A), RS1014094429 (15:23688378 C>G,T), RS1014126914 (15:23688859 A>G), RS1014238608 (15:23685498 A>G)

Disease associations

OMIM: gene MIM:602117 | disease phenotypes: MIM:176270

GenCC curated gene-disease

Disease	Classification	Inheritance
Prader-Willi syndrome	Limited	Autosomal dominant

Mondo (1): Prader-Willi syndrome (MONDO:0008300)

Orphanet (1): Prader-Willi syndrome (Orphanet:739)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000219	Thin upper lip vermilion
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000819	Diabetes mellitus
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000826	Precocious puberty
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001010	Hypopigmentation of the skin
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001319	Neonatal hypotonia
HP:0001328	Specific learning disability
HP:0001385	Hip dysplasia
HP:0001508	Failure to thrive
HP:0001513	Obesity

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002755_9	Depressive symptoms (SSRI exposure interaction)	5.000000e-06
GCST005648_30	Serum metabolite concentrations in chronic kidney disease	5.000000e-08
GCST008368_20	Plasma anti-thyroid peroxidase levels	4.000000e-06
GCST010242_271	HDL cholesterol levels	2.000000e-09
GCST010989_69	Body size at age 10	3.000000e-11
GCST011677_1	Parkinson’s disease (age of onset)	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement
EFO:0007010	drug use measurement
EFO:0007011	SSRI use measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004847	age at onset

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011218	Prader-Willi Syndrome	C10.597.606.360.690; C16.131.077.730; C16.131.260.700; C16.320.180.700; C16.320.447.500; C18.654.726.750.500.740

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases methylation	4
Decitabine	decreases reaction, increases expression, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tobacco tar	decreases reaction, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Rosiglitazone	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01298180	PHASE4	COMPLETED	Is There a Sensibility Increased in the Growth Hormone at Child With Prader-Willi Syndrome?
NCT01542242	PHASE4	TERMINATED	Liraglutide Use in Prader-Willi Syndrome
NCT03031626	PHASE4	COMPLETED	Oxygen Versus Medical Air for Treatment of CSA in Prader Will Syndrome
NCT03616509	PHASE4	COMPLETED	GH in Adults With PWS, Effect on Hypotonia Evaluated by Functional MRI, Relationship With Strength and Body Composition
NCT04066088	PHASE4	WITHDRAWN	Dose Clinical Trial of Guanfacine Extended Release for the Reduction of Aggression and Self-injuries Behavior Associated With Prader-Willi Syndrome
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06901245	PHASE4	RECRUITING	Tirzepatide in PWS, HO and GNSO
NCT00175305	PHASE3	TERMINATED	Prader-Willi Syndrome and Appetite
NCT00444964	PHASE3	COMPLETED	Growth Hormone Use in Adults With Prader-Willi Syndrome
NCT00603109	PHASE3	TERMINATED	Effect of Rimonabant on Weight Gain and Body Composition in Adults With Prader Willi Syndrome
NCT02179151	PHASE3	TERMINATED	Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Beloranib) in Obese Subjects With Prader-Willi Syndrome
NCT02204163	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Eutropin in Prader-Willi Syndrome
NCT02810483	PHASE3	TERMINATED	Study of the Efficacy of Topiramate in Patients With Prader Willi Syndrome Over 8 Weeks
NCT03440814	PHASE3	COMPLETED	A Study of Diazoxide Choline in Patients With Prader-Willi Syndrome
NCT03554031	PHASE3	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone Injection in Patients With Prader-Willi Syndrome
NCT03649477	PHASE3	COMPLETED	Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome
NCT03714373	PHASE3	COMPLETED	Open-Label Extension Study of DCCR in PWS Followed by Double-Blind, Placebo-Controlled, Randomized Withdrawal Period
NCT04086810	PHASE3	WITHDRAWN	An Open-Label Study of DCCR Tablet in Patients With PWS
NCT04283578	PHASE3	COMPLETED	Oxytocin Treatment in Neonates and Infants With Prader-Willi Syndrome
NCT04697381	PHASE3	COMPLETED	Study of the Efficacy and Safety of Somatropin in Japanese Participants With PWS
NCT05032326	PHASE3	UNKNOWN	Long-term Interventional Follow-up Study of Children With Prader-Willi Syndrome Included in the OTBB3 Clinical Trial
NCT05387798	PHASE3	WITHDRAWN	A Phase 3 Extension Study of RAD011 (Cannabidiol Oral Solution) in Patients With Prader-Willi Syndrome
NCT05701774	PHASE3	ACTIVE_NOT_RECRUITING	Open-Label Extension Study of DCCR in Patients With Prader-Willi Syndrome
NCT06144645	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Evaluation of Non-Invasive Vagus Nerve Stimulation for Temper Outbursts in People With PWS
NCT06366464	PHASE3	RECRUITING	A Study of Pitolisant in Patients With Prader-Willi Syndrome
NCT06828861	PHASE3	SUSPENDED	ARD-101 for Treatment of PWS: The Hunger Elimination or Reduction Objective Trial
NCT07197034	PHASE3	SUSPENDED	The Hunger Elimination or Reduction Objective (HERO ) Open -Label Extension (OLE) Trial
NCT07219485	PHASE3	ENROLLING_BY_INVITATION	A Study of Pitolisant in Participants With Prader-Willi Syndrome
NCT01038570	PHASE2	COMPLETED	Comparative Study Between Prader-Willi Patients Who Take Oxytocin Versus Placebo
NCT01818921	PHASE2	COMPLETED	An Efficacy, Safety, and Pharmacokinetics Study of Beloranib in Obese Subjects With Prader-Willi Syndrome
NCT02311673	PHASE2	COMPLETED	Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome
NCT02629991	PHASE2	COMPLETED	Oxytocin vs. Placebo for the Treatment Hyperphagia in Children and Adolescents With Prader-Willi Syndrome
NCT02844933	PHASE2	TERMINATED	Cannabidiol Oral Solution for the Treatment of Patients With Prader-Willi Syndrome
NCT02893618	PHASE2	UNKNOWN	A 5 Treatment Period Pharmacokinetic Study Evaluating Dose Proportionality and Food Effects of Diazoxide Choline Controlled-Release Tablet (DCCR)
NCT03197662	PHASE2	COMPLETED	Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome
NCT03274856	PHASE2	COMPLETED	A Study of GLWL-01 in Patients With Prader-Willi Syndrome
NCT03458416	PHASE2	TERMINATED	A Study to Assess the Long-Term Safety of Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Participants With Prader-Willi Syndrome
NCT03831425	PHASE2	WITHDRAWN	Mitochondrial Complex I Dysfunction in PWS
NCT03848481	PHASE2	TERMINATED	CBDV vs Placebo in Children and Adults up to Age 30 With Prader-Willi Syndrome (PWS)
NCT04257929	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension