Mobius syndrome

Summary

Mobius syndrome (MONDO:0008006) is a disease caused by variants in PLXND1 and REV3L, with 23 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal genes: PLXND1 (GenCC Strong), REV3L (GenCC Strong)
• Cohort genes: 23
• ClinVar variants: 29
• Phenotypes (HPO): 42
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		300	Worldwide	Validated
Point prevalence	1-9 / 100 000	0.3	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.27	Italy	Validated
Prevalence at birth	1-9 / 100 000	2.12	Netherlands	Validated
Prevalence at birth	<1 / 1 000 000	0.06	Italy	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0000194	Open mouth	Very frequent (80-99%)
HP:0000298	Mask-like facies	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000602	Ophthalmoplegia	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Very frequent (80-99%)
HP:0006824	Cranial nerve paralysis	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0010628	Facial palsy	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0009751	Aplasia of the pectoralis major muscle	Frequent (30-79%)
HP:0000044	Hypogonadotropic hypogonadism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000498	Blepharitis	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0004050	Absent hand	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0004408	Abnormality of the sense of smell	Occasional (5-29%)
HP:0005914	Aplasia/Hypoplasia involving the metacarpal bones	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0006501	Aplasia/Hypoplasia of the radius	Occasional (5-29%)
HP:0007565	Multiple cafe-au-lait spots	Occasional (5-29%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Occasional (5-29%)
HP:0009804	Tooth agenesis	Occasional (5-29%)
HP:0010295	Aplasia/Hypoplasia of the tongue	Occasional (5-29%)
HP:0040071	Abnormal morphology of ulna	Occasional (5-29%)
HP:0100783	Breast aplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Mobius syndrome
Mondo ID	MONDO:0008006
MeSH	D020331
OMIM	157900
Orphanet	570
DOID	DOID:13501
NCIT	C84893
SNOMED CT	89444000
UMLS	C0221060
MedGen	66357
GARD	0008549
MedDRA	10027789, 10030069
NORD	1453
Is cancer (heuristic)	no

Also known as: absence or underdevelopment of the 6th and 7th cranial nerves · congenital facial diplegia · congenital facial diplegia syndrome · congenital oculofacial paralysis · MBS · Mobius syndrome · Moebius sequence · Moebius Syndrome · Moebius syndrome · Moebius syndrome, Isolated cases · Möbius syndrome · oromandibular-limb hypogenesis spectrum

Data availability: 29 ClinVar variants · 8 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › cranial nerve neuropathy › facial nerve disorder › Mobius syndrome

Related subtypes (8): facial neuralgia, geniculate ganglionitis, facial nerve neoplasm, Bell’s palsy, facial hemiatrophy, clonic hemifacial spasm, Melkersson-Rosenthal syndrome, isolated facial myokymia

Subtypes (1): Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

29 retrieved; paginated sample, class counts are floors:

15 likely benign, 7 uncertain significance, 2 likely pathogenic, 2 benign, 2 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1708248	NM_001822.7(CHN1):c.643G>A (p.Gly215Arg)	CHN1	Likely pathogenic	criteria provided, single submitter
267357	NM_001375380.1(EBF3):c.577A>G (p.Lys193Glu)	EBF3	Likely pathogenic	criteria provided, single submitter
254101	NM_005068.3(SIM1):c.2119G>C (p.Asp707His)	SIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
254118	NM_007037.6(ADAMTS8):c.2109C>A (p.Tyr703Ter)	ADAMTS8	Uncertain significance	no assertion criteria provided
254119	NM_003458.4(BSN):c.7374GCAGCAGCAGCT[1] (p.2459QQQL[1])	BSN	Uncertain significance	no assertion criteria provided
254120	NM_001351601.3(INTS6L):c.359del (p.Phe119_Leu120insTer)	INTS6L	Uncertain significance	no assertion criteria provided
254123	NM_001277325.2(NPIPA5):c.962C>T (p.Pro321Leu)	NPIPA5	Uncertain significance	criteria provided, single submitter
1709603	NM_015103.3(PLXND1):c.2467C>A (p.Pro823Thr)	PLXND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
254114	NM_003738.5(PTCH2):c.2018G>T (p.Arg673Leu)	PTCH2	Uncertain significance	criteria provided, single submitter
254121	NM_001002836.4(ZNF787):c.1086G>C (p.Glu362Asp)	ZNF787	Uncertain significance	no assertion criteria provided
254116	NM_000479.5(AMH):c.350G>A (p.Arg117Gln)	AMH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
254103	NM_181708.3(BCDIN3D):c.23A>G (p.Asp8Gly)	BCDIN3D	Benign	criteria provided, multiple submitters, no conflicts
254106	NM_001797.4(CDH11):c.95G>A (p.Arg32Gln)	CDH11	Likely benign	no assertion criteria provided
254107	NM_001797.4(CDH11):c.1247C>T (p.Pro416Leu)	CDH11	Likely benign	no assertion criteria provided
254110	NM_153606.4(GARIN4):c.1465T>C (p.Ser489Pro)	GARIN4	Likely benign	no assertion criteria provided
254111	NM_153606.4(GARIN4):c.1475G>A (p.Gly492Asp)	GARIN4	Likely benign	no assertion criteria provided
254098	NM_001348768.2(HECW2):c.3394G>A (p.Asp1132Asn)	HECW2	Likely benign	no assertion criteria provided
254099	NM_001348768.2(HECW2):c.2264AAG[2] (p.Glu757del)	HECW2	Likely benign	no assertion criteria provided
254100	NM_001348768.2(HECW2):c.1249_1251del (p.Asn417del)	HECW2	Likely benign	no assertion criteria provided
254117	NM_014424.5(HSPB7):c.442A>G (p.Thr148Ala)	HSPB7	Likely benign	no assertion criteria provided
254109	NM_032138.7(KBTBD7):c.1208A>C (p.Lys403Thr)	KBTBD6-DT	Likely benign	no assertion criteria provided
254108	NM_032138.7(KBTBD7):c.1496C>G (p.Pro499Arg)	KBTBD7	Likely benign	no assertion criteria provided
254122	NM_001348716.2(KDM6B):c.753ACC[15] (p.Pro263_Pro264dup)	KDM6B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
254104	NM_006428.5(MRPL28):c.610G>A (p.Val204Met)	MRPL28	Likely benign	no assertion criteria provided
254105	NM_006428.5(MRPL28):c.176G>C (p.Arg59Pro)	MRPL28	Likely benign	no assertion criteria provided
254112	NM_004573.3(PLCB2):c.1154A>G (p.Lys385Arg)	PLCB2	Likely benign	no assertion criteria provided
254113	NM_004573.3(PLCB2):c.2585C>A (p.Thr862Lys)	PLCB2	Likely benign	no assertion criteria provided
254115	NM_003738.5(PTCH2):c.1156A>T (p.Ile386Phe)	PTCH2	Likely benign	no assertion criteria provided
254102	NM_005068.3(SIM1):c.1994G>A (p.Arg665His)	SIM1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PLXND1	Strong	Autosomal dominant	Mobius syndrome	7
REV3L	Strong	Autosomal dominant	Mobius syndrome	4
LMX1A	Limited	Autosomal dominant	Mobius syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLXND1	Orphanet:3384	Common arterial trunk
PLXND1	Orphanet:570	Moebius syndrome
REV3L	Orphanet:570	Moebius syndrome
SIM1	Orphanet:171829	6q16 microdeletion syndrome
SIM1	Orphanet:369873	Obesity due to SIM1 deficiency
SIM1	Orphanet:398079	SIM1-related Prader-Willi-like syndrome
CDH11	Orphanet:1299	Branchioskeletogenital syndrome
EBF3	Orphanet:658843	Developmental delay-ataxia-hypotonia-facial dysmorphism syndrome
EBF3	Orphanet:96148	Distal deletion 10q syndrome
CHN1	Orphanet:233	Duane retraction syndrome
AMH	Orphanet:2856	Persistent Müllerian duct syndrome
PTCH2	Orphanet:141276	Tessier number 7 facial cleft
PTCH2	Orphanet:377	Gorlin syndrome

Cohort genes → proteins

23 cohort genes, 22 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	23

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLXND1	HGNC:9107	ENSG00000004399	Q9Y4D7	Plexin-D1	gencc,clinvar
LMX1A	HGNC:6653	ENSG00000162761	Q8TE12	LIM homeobox transcription factor 1-alpha	gencc
REV3L	HGNC:9968	ENSG00000009413	O60673	DNA polymerase zeta catalytic subunit	gencc
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	clinvar
BSN	HGNC:1117	ENSG00000164061	Q9UPA5	Protein bassoon	clinvar
MRPL28	HGNC:14484	ENSG00000086504	Q13084	Large ribosomal subunit protein bL28m	clinvar
CDH11	HGNC:1750	ENSG00000140937	P55287	Cadherin-11	clinvar
EBF3	HGNC:19087	ENSG00000108001	Q9H4W6	Transcription factor COE3	clinvar
CHN1	HGNC:1943	ENSG00000128656	P15882	N-chimaerin	clinvar
ADAMTS8	HGNC:224	ENSG00000134917	Q9UP79	A disintegrin and metalloproteinase with thrombospondin motifs 8	clinvar
KBTBD7	HGNC:25266	ENSG00000120696	Q8WVZ9	Kelch repeat and BTB domain-containing protein 7	clinvar
GARIN4	HGNC:26541	ENSG00000162771	Q8IYT1	Golgi-associated RAB2 interactor protein 4	clinvar
ZNF787	HGNC:26998	ENSG00000142409	Q6DD87	Zinc finger protein 787	clinvar
BCDIN3D	HGNC:27050	ENSG00000186666	Q7Z5W3	RNA 5’-monophosphate methyltransferase	clinvar
INTS6L	HGNC:27334	ENSG00000165359	Q5JSJ4	Integrator complex subunit 6-like	clinvar
KDM6B	HGNC:29012	ENSG00000132510	O15054	Lysine-specific demethylase 6B	clinvar
HECW2	HGNC:29853	ENSG00000138411	Q9P2P5	E3 ubiquitin-protein ligase HECW2	clinvar
NPIPA5	HGNC:41980	ENSG00000183793	E9PKD4	Nuclear pore complex-interacting protein family member A5	clinvar
AMH	HGNC:464	ENSG00000104899	P03971	Anti-Muellerian hormone	clinvar
HSPB7	HGNC:5249	ENSG00000173641	Q9UBY9	Heat shock protein beta-7	clinvar
KBTBD6-DT	HGNC:56824	ENSG00000278390		KBTBD6 divergent transcript	clinvar
PLCB2	HGNC:9055	ENSG00000137841	Q00722	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2	clinvar
PTCH2	HGNC:9586	ENSG00000117425	Q9Y6C5	Protein patched homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLXND1	Plexin-D1	Cell surface receptor for SEMA4A and for class 3 semaphorins, such as SEMA3A, SEMA3C and SEMA3E.
LMX1A	LIM homeobox transcription factor 1-alpha	Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter.
REV3L	DNA polymerase zeta catalytic subunit	Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS).
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
BSN	Protein bassoon	Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.
CDH11	Cadherin-11	Cadherins are calcium-dependent cell adhesion proteins.
EBF3	Transcription factor COE3	Transcriptional activator.
CHN1	N-chimaerin	GTPase-activating protein for p21-rac and a phorbol ester receptor.
ADAMTS8	A disintegrin and metalloproteinase with thrombospondin motifs 8	Has anti-angiogenic properties.
KBTBD7	Kelch repeat and BTB domain-containing protein 7	As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions as a substrate adapter for the RAC1 guanine exchange factor (GEF) TIAM1, mediating its ‘Lys-48’ ubiquitination and proteasomal degradation.
GARIN4	Golgi-associated RAB2 interactor protein 4	RAB2B effector protein required for the compacted Golgi morphology, probably through interaction with small GTPase RAB2B.
ZNF787	Zinc finger protein 787	May be involved in transcriptional regulation.
BCDIN3D	RNA 5’-monophosphate methyltransferase	O-methyltransferase that specifically monomethylates 5’-monophosphate of cytoplasmic histidyl tRNA (tRNA(His)), acting as a capping enzyme by protecting tRNA(His) from cleavage by DICER1.
KDM6B	Lysine-specific demethylase 6B	Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code.
HECW2	E3 ubiquitin-protein ligase HECW2	E3 ubiquitin-protein ligase that mediates ubiquitination of TP73.
AMH	Anti-Muellerian hormone	The anti-Muellerian hormone (AMH) plays an important role in several reproductive functions.
PLCB2	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
PTCH2	Protein patched homolog 2	Plays a role in the control of cellular growth.

Protein-family classification

Druggable: 5 · Difficult: 8 · Unknown: 10 · Druggable fraction: 0.22

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	6	2.1×	0.309
Protease	1	1.6×	0.662
Enzyme (other)	3	1.6×	0.662
Scaffold/PPI	2	1.5×	0.662
Antibody/Immunoglobulin	1	1.3×	0.662
Other/Unknown	10	0.8×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLXND1	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom
LMX1A	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
REV3L	Transcription factor	no		DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B
SIM1	Transcription factor	no		PAS, PAC, SIM_C
BSN	Transcription factor	no		Znf_piccolo, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
MRPL28	Other/Unknown	no		Ribosomal_bL28, Ribosomal_bL28/bL31-like_sf, Ribosomal_bL28_sf
CDH11	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
EBF3	Transcription factor	no		IPT_dom, Transcription_factor_COE, Ig-like_fold
CHN1	Scaffold/PPI	no		RhoGAP_dom, SH2, PKC_DAG/PE
ADAMTS8	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
KBTBD7	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
GARIN4	Other/Unknown	no		GARIL-like_Rab2B-bd
ZNF787	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
BCDIN3D	Enzyme (other)	yes	2.1.1.B140	Bin3_C, BIN3_SAM-bd_dom, SAM-dependent_MTases_sf
INTS6L	Other/Unknown	no		VWF_A, INT_SG_DDX_CT_C, vWFA_dom_sf
KDM6B	Enzyme (other)	yes	1.14.11.68	JmjC_dom, KDM6_GATAL_sf, KDM6A_B-like_GATAL
HECW2	Scaffold/PPI	no		C2_dom, HECT_dom, WW_dom
NPIPA5	Other/Unknown	no		NPIP, NPIP_N
AMH	Other/Unknown	no		TGF-b_C, AMH_N, TGFb_CS
HSPB7	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
KBTBD6-DT	Other/Unknown	no
PLCB2	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
PTCH2	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD

Expression context

Cohort genes with no expression data: 0.

19 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	23
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	6
middle temporal gyrus	4
apex of heart	3
left testis	3
right hemisphere of cerebellum	3
upper lobe of left lung	2
sperm	2
calcaneal tendon	2
Brodmann (1909) area 23	2
cerebellar cortex	2
cerebellar hemisphere	2
left ventricle myocardium	2
right coronary artery	1
right lung	1
endometrium	1
skin of hip	1
biceps brachii	1
renal medulla	1
skeletal muscle tissue of biceps brachii	1
frontal pole	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLXND1	278	ubiquitous	marker	upper lobe of left lung, right coronary artery, right lung
LMX1A	92	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, sperm, apex of heart
REV3L	289	ubiquitous	marker	calcaneal tendon, skin of hip, endometrium
SIM1	76	broad	yes	renal medulla, skeletal muscle tissue of biceps brachii, biceps brachii
BSN	156	broad	marker	frontal pole, paraflocculus, middle temporal gyrus
MRPL28	286	ubiquitous	marker	apex of heart, left testis, right testis
CDH11	277	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, tibia
EBF3	193	broad	marker	tibialis anterior, subcutaneous adipose tissue, tendon of biceps brachii
CHN1	279	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
ADAMTS8	197	tissue_specific	marker	middle temporal gyrus, upper lobe of left lung, upper lobe of lung
KBTBD7	250	ubiquitous	marker	secondary oocyte, oocyte, buccal mucosa cell
GARIN4	134	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, left testis
ZNF787	237	ubiquitous	marker	hindlimb stylopod muscle, mucosa of transverse colon, right uterine tube
BCDIN3D	180	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, islet of Langerhans
INTS6L	210	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
KDM6B	264	ubiquitous	marker	blood, sural nerve, cortical plate
HECW2	227	ubiquitous	marker	left ventricle myocardium, Brodmann (1909) area 23, middle temporal gyrus
NPIPA5	134		yes	primary visual cortex, right hemisphere of cerebellum, cerebellar cortex
AMH	160	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right hemisphere of cerebellum, cerebellar hemisphere
HSPB7	209	broad	marker	left ventricle myocardium, apex of heart, heart right ventricle
KBTBD6-DT	133		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, calcaneal tendon
PLCB2	190	broad	marker	granulocyte, monocyte, mononuclear cell
PTCH2	162	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right ovary

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDM6B	8,241
CDH11	2,302
REV3L	2,276
HECW2	2,127
PLCB2	2,123
BSN	2,060
MRPL28	1,916
AMH	1,556
KBTBD7	1,463
PLXND1	1,454

Intra-cohort edges

A	B	Sources
GARIN4	INTS6L	string_interaction
GARIN4	KBTBD7	string_interaction
GARIN4	NPIPA5	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 10 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL28	Q13084	86
REV3L	O60673	14
KDM6B	O15054	6
LMX1A	Q8TE12	3
AMH	P03971	3
EBF3	Q9H4W6	2
CHN1	P15882	2
HSPB7	Q9UBY9	2
PLCB2	Q00722	2
PLXND1	Q9Y4D7	1
BCDIN3D	Q7Z5W3	1
HECW2	Q9P2P5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KBTBD7	Q8WVZ9	81.03
ADAMTS8	Q9UP79	80.22
PTCH2	Q9Y6C5	79.25
CDH11	P55287	77.65
INTS6L	Q5JSJ4	68.53
ZNF787	Q6DD87	65.10
SIM1	P81133	60.70
GARIN4	Q8IYT1	53.14
NPIPA5	E9PKD4	52.14
BSN	Q9UPA5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 78. Enrichment computed across 23 evidence-associated genes (14 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	116.5×	0.110	PTCH2
CDH11 homotypic and heterotypic interactions	1	116.5×	0.110	CDH11
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	102.0×	0.110	PLCB2
Regulation of CDH11 mRNA translation by microRNAs	1	90.6×	0.110	CDH11
Acetylcholine regulates insulin secretion	1	81.6×	0.110	PLCB2
Regulation of CDH11 function	1	74.2×	0.110	CDH11
Regulation of CDH11 gene transcription	1	74.2×	0.110	CDH11
Regulation of CDH11 Expression and Function	1	58.3×	0.110	CDH11
Translesion synthesis by REV1	1	51.0×	0.110	REV3L
Transcriptional regulation of testis differentiation	1	51.0×	0.110	AMH
Maternal to zygotic transition (MZT)	1	51.0×	0.110	KDM6B
Translesion synthesis by POLI	1	48.0×	0.110	REV3L
Regulation of Homotypic Cell-Cell Adhesion	1	48.0×	0.110	CDH11
Regulation of Expression and Function of Type II Classical Cadherins	1	48.0×	0.110	CDH11
Translesion synthesis by POLK	1	45.3×	0.110	REV3L
Other semaphorin interactions	1	42.9×	0.110	PLXND1
G beta:gamma signalling through PLC beta	1	40.8×	0.110	PLCB2
Presynaptic function of Kainate receptors	1	38.8×	0.110	PLCB2
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	35.5×	0.114	CDH11
MicroRNA (miRNA) biogenesis	1	32.6×	0.116	BCDIN3D
NOTCH3 Intracellular Domain Regulates Transcription	1	31.4×	0.116	PLXND1
Synthesis of IP3 and IP4 in the cytosol	1	30.2×	0.116	PLCB2
Signaling by BMP	1	25.5×	0.125	AMH
Gene Silencing by RNA	1	25.5×	0.125	BCDIN3D
Defective B3GALTL causes PpS	1	22.1×	0.130	ADAMTS8
Sensory processing of sound	1	22.1×	0.130	BSN
O-glycosylation of TSR domain-containing proteins	1	21.5×	0.130	ADAMTS8
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	19.9×	0.130	PLCB2
PLC beta mediated events	1	19.0×	0.130	PLCB2
RND2 GTPase cycle	1	18.5×	0.130	PLXND1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aortic valve formation	1	401.2×	0.070	CDH11
synaptic target recognition	1	401.2×	0.070	PLXND1
development of primary male sexual characteristics	1	267.5×	0.070	AMH
presynaptic active zone assembly	1	267.5×	0.070	BSN
negative regulation of ovarian follicle development	1	267.5×	0.070	AMH
negative regulation of pre-miRNA processing	1	267.5×	0.070	BCDIN3D
preantral ovarian follicle growth	1	200.6×	0.070	AMH
dichotomous subdivision of terminal units involved in salivary gland branching	1	200.6×	0.070	PLXND1
Mullerian duct regression	1	160.5×	0.070	AMH
epidermal cell fate specification	1	160.5×	0.070	PTCH2
response to fungicide	1	133.8×	0.070	KDM6B
anti-Mullerian hormone receptor signaling pathway	1	133.8×	0.070	AMH
regulation of cell growth	2	21.1×	0.070	LMX1A, PTCH2
modulation of chemical synaptic transmission	2	17.4×	0.070	BSN, CDH11
cell morphogenesis	2	15.0×	0.070	CDH11, GARIN4
corticospinal tract morphogenesis	1	114.6×	0.071	CDH11
positive regulation of epidermal cell differentiation	1	100.3×	0.071	PTCH2
regulation of Rac protein signal transduction	1	89.2×	0.071	KBTBD7
olfactory behavior	1	89.2×	0.071	LMX1A
RNA methylation	1	80.2×	0.071	BCDIN3D
cardiac septum development	1	80.2×	0.071	PLXND1
gonadal mesoderm development	1	80.2×	0.071	AMH
sex determination	1	80.2×	0.071	AMH
penetration of zona pellucida	1	73.0×	0.071	GARIN4
error-prone translesion synthesis	1	73.0×	0.071	REV3L
mesodermal cell differentiation	1	73.0×	0.071	KDM6B
miRNA metabolic process	1	66.9×	0.072	BCDIN3D
synaptic vesicle clustering	1	66.9×	0.072	BSN
snRNA 3’-end processing	1	61.7×	0.072	INTS6L
Leydig cell differentiation	1	57.3×	0.072	AMH

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 22

Druggability breadth: 3 of 23 evidence-associated genes (13%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KDM6B	DEFERASIROX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM6B	5	4
PLXND1	0	0
LMX1A	0	0
REV3L	0	0
SIM1	0	0
BSN	0	0
MRPL28	0	0
CDH11	0	0
EBF3	0	0
CHN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DEFERASIROX	4	KDM6B
TANESPIMYCIN	3	KDM6B
GELDANAMYCIN	2	KDM6B
ALVESPIMYCIN	2	KDM6B
ZAVONDEMSTAT	2	KDM6B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KDM6B	75	Binding:73, Functional:2
BCDIN3D	27	Binding:27
ZNF787	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BCDIN3D	2.1.1.B140
KDM6B	1.14.11.68, 1.14.18.B1	[histone H3]-trimethyl-L-lysine27 demethylase,
PLCB2	3.1.4.11	phosphoinositide phospholipase C

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DEFERASIROX	4	KDM6B
TANESPIMYCIN	3	KDM6B
GELDANAMYCIN	2	KDM6B
ALVESPIMYCIN	2	KDM6B
ZAVONDEMSTAT	2	KDM6B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM6B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	PLXND1, BCDIN3D, PLCB2
D	Druggable family + AlphaFold only, no drug	1	ADAMTS8
E	Difficult family or no structure, no drug	18	LMX1A, REV3L, SIM1, BSN, MRPL28, CDH11, EBF3, CHN1, KBTBD7, GARIN4 (+8 more)

Undrugged target profiles

22 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PLXND1	0	—
LMX1A	0	—
REV3L	0	—
SIM1	0	—
BSN	0	—
MRPL28	0	—
CDH11	0	—
EBF3	0	—
CHN1	0	—
ADAMTS8	0	—
KBTBD7	0	—
GARIN4	0	—
ZNF787	1	—
BCDIN3D	27	—
INTS6L	0	—
HECW2	0	—
NPIPA5	0	—
AMH	0	—
HSPB7	0	—
KBTBD6-DT	0	—
PLCB2	0	—
PTCH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies