FG syndrome 1

Summary

FG syndrome 1 (MONDO:0010590) is a disease caused by MED12 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: MED12 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 121
• Phenotypes (HPO): 72

Clinical features

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000269	Prominent occiput	Frequent (30-79%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000378	Cupped ear	Frequent (30-79%)
HP:0000402	Stenosis of the external auditory canal	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000475	Broad neck	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000609	Optic nerve hypoplasia	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000766	Abnormal sternum morphology	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001357	Plagiocephaly	Frequent (30-79%)
HP:0001533	Slender build	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0001837	Broad toe	Frequent (30-79%)
HP:0002021	Pyloric stenosis	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002236	Frontal upsweep of hair	Frequent (30-79%)
HP:0002250	Abnormal large intestine morphology	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002761	Generalized joint laxity	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004492	Widely patent fontanelles and sutures	Frequent (30-79%)
HP:0004785	Malrotation of colon	Frequent (30-79%)
HP:0005852	Limited elbow extension and supination	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0008551	Microtia	Frequent (30-79%)
HP:0008935	Generalized neonatal hypotonia	Frequent (30-79%)
HP:0011090	Fused teeth	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0012506	Small pituitary gland	Frequent (30-79%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	FG syndrome 1
Mondo ID	MONDO:0010590
OMIM	305450
Orphanet	93932
SNOMED CT	1237179007
UMLS	C5399762
MedGen	1768809
GARD	0002317
NORD	1142
Is cancer (heuristic)	no

Also known as: FG syndrome 1 · FG syndrome caused by mutation in MED12 · FG Syndrome Type 1 · MED12 FG syndrome · mental retardation, large head, imperforate anus, congenital hypotonia, and partial agenesis of corpus callosum · OKS · Opitz-Kaveggia syndrome · Opitz-Kaveggia syndrome, X-linked recessive

Data availability: 121 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › FG syndrome › FG syndrome 1

Related subtypes (5): FG syndrome 2, FG syndrome 3, FG syndrome 4, FG syndrome 5, Aarskog-Scott syndrome, X-linked

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

121 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 20 conflicting classifications of pathogenicity, 15 not provided, 13 pathogenic, 10 likely pathogenic, 7 pathogenic/likely pathogenic, 7 benign/likely benign, 6 benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
452540	NM_005120.3(MED12):c.1547G>A (p.Arg516His)	LOC126863275	Pathogenic	criteria provided, multiple submitters, no conflicts
11520	NM_005120.3(MED12):c.2881C>T (p.Arg961Trp)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11521	NM_005120.3(MED12):c.3020A>G (p.Asn1007Ser)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1201510	NM_005120.3(MED12):c.3646G>A (p.Val1216Met)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210231	NM_005120.3(MED12):c.514G>C (p.Glu172Gln)	MED12	Pathogenic	criteria provided, single submitter
1210232	NM_005120.3(MED12):c.1249-1G>C	MED12	Pathogenic	criteria provided, single submitter
1210242	NM_005120.3(MED12):c.3412C>T (p.Arg1138Trp)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210246	NM_005120.3(MED12):c.4070G>A (p.Arg1357His)	MED12	Pathogenic	criteria provided, multiple submitters, no conflicts
1210248	NM_005120.3(MED12):c.4903_4906delinsCCAGCA (p.Val1635fs)	MED12	Pathogenic	no assertion criteria provided
1210249	NM_005120.3(MED12):c.5111G>A (p.Trp1704Ter)	MED12	Pathogenic	no assertion criteria provided
1210250	NM_005120.3(MED12):c.5622C>A (p.Tyr1874Ter)	MED12	Pathogenic	no assertion criteria provided
1210252	NM_005120.3(MED12):c.6169C>T (p.Gln2057Ter)	MED12	Pathogenic	criteria provided, single submitter
213640	NM_005120.3(MED12):c.3883C>T (p.Arg1295Cys)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425298	NC_000023.10:g.(?70337406)(70363304_?)del	MED12	Pathogenic	criteria provided, single submitter
252964	NM_005120.3(MED12):c.5898dup (p.Ser1967fs)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382729	NM_005120.3(MED12):c.3129del (p.Ser1044fs)	MED12	Pathogenic	criteria provided, single submitter
50280	NM_005120.3(MED12):c.3493T>C (p.Ser1165Pro)	MED12	Pathogenic	no assertion criteria provided
50281	NM_005120.3(MED12):c.5185C>A (p.His1729Asn)	MED12	Pathogenic	no assertion criteria provided
521365	NM_005120.3(MED12):c.3884G>A (p.Arg1295His)	MED12	Pathogenic	criteria provided, multiple submitters, no conflicts
522111	NM_005120.3(MED12):c.887G>A (p.Arg296Gln)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619013	NM_005120.3(MED12):c.1546C>T (p.Arg516Cys)	LOC126863275	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210236	NM_005120.3(MED12):c.2669T>A (p.Ile890Asn)	MED12	Likely pathogenic	no assertion criteria provided
1210257	NM_005120.3(MED12):c.6448C>T (p.Gln2150Ter)	MED12	Likely pathogenic	criteria provided, single submitter
196905	NM_005120.3(MED12):c.4669T>C (p.Trp1557Arg)	MED12	Likely pathogenic	criteria provided, single submitter
225253	NM_005120.3(MED12):c.1862G>A (p.Arg621Gln)	MED12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499563	NM_005120.3(MED12):c.4439C>T (p.Pro1480Leu)	MED12	Likely pathogenic	criteria provided, single submitter
2576549	NM_005120.3(MED12):c.4863+1G>A	MED12	Likely pathogenic	criteria provided, single submitter
427070	NM_005120.3(MED12):c.6476A>C (p.Gln2159Pro)	MED12	Likely pathogenic	criteria provided, single submitter
666337	NM_005120.3(MED12):c.3505G>T (p.Ala1169Ser)	MED12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
804025	NM_005120.3(MED12):c.224G>C (p.Ser75Thr)	MED12	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 7 · 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
MED12	Definitive	Autosomal dominant	autosomal dominant optic atrophy, classic form	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
GJB1	Orphanet:101075	X-linked Charcot-Marie-Tooth disease type 1
GJB1	Orphanet:1175	X-linked progressive cerebellar ataxia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gencc,clinvar
CXorf65	HGNC:33713	ENSG00000204165	A6NEN9	Uncharacterized protein CXorf65	clinvar
GJB1	HGNC:4283	ENSG00000169562	P08034	Gap junction beta-1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
GJB1	Gap junction beta-1 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
CXorf65	Other/Unknown	no		CXorf65-like
GJB1	Other/Unknown	no		Connexin, Connexin32, Connexin_N

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
granulocyte	1
left testis	1
testis	1
C1 segment of cervical spinal cord	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
CXorf65	122	tissue_specific	yes	granulocyte, left testis, testis
GJB1	207	broad	marker	right lobe of liver, C1 segment of cervical spinal cord, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED12	3,322
GJB1	1,494
CXorf65	207

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB1	P08034	15
MED12	Q93074	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CXorf65	A6NEN9	82.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oligomerization of connexins into connexons	1	1903.3×	0.006	GJB1
Transport of connexins along the secretory pathway	1	1903.3×	0.006	GJB1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.031	GJB1
Gap junction assembly	1	146.4×	0.031	GJB1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.031	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.031	MED12
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.031	MED12
RSV-host interactions	1	78.2×	0.031	MED12
Adipogenesis	1	78.2×	0.031	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.031	MED12
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.031	MED12
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.031	MED12
PPARA activates gene expression	1	47.2×	0.039	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.041	MED12
Epigenetic regulation of gene expression	1	35.7×	0.045	MED12
Metabolism of lipids	1	15.8×	0.090	MED12
Viral Infection Pathways	1	15.4×	0.090	MED12
Infectious disease	1	12.4×	0.105	MED12
RNA Polymerase II Transcription	1	11.3×	0.110	MED12
Gene expression (Transcription)	1	8.9×	0.131	MED12
Generic Transcription Pathway	1	7.5×	0.146	MED12
Developmental Biology	1	7.2×	0.146	MED12
Disease	1	6.5×	0.153	MED12
Metabolism	1	5.8×	0.165	MED12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axis elongation involved in somitogenesis	1	1872.4×	0.011	MED12
gap junction assembly	1	702.2×	0.011	GJB1
embryonic neurocranium morphogenesis	1	624.1×	0.011	MED12
Schwann cell development	1	351.1×	0.012	MED12
embryonic brain development	1	267.5×	0.012	MED12
post-anal tail morphogenesis	1	244.2×	0.012	MED12
endoderm development	1	208.1×	0.012	MED12
oligodendrocyte development	1	200.6×	0.012	MED12
spinal cord development	1	170.2×	0.013	MED12
Wnt signaling pathway, planar cell polarity pathway	1	151.8×	0.013	MED12
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.020	MED12
somatic stem cell population maintenance	1	82.6×	0.020	MED12
neural tube closure	1	62.4×	0.025	MED12
heart development	1	26.2×	0.053	MED12
transcription by RNA polymerase II	1	23.5×	0.053	CXorf65
cell-cell signaling	1	23.2×	0.053	GJB1
nervous system development	1	15.3×	0.075	GJB1
protein ubiquitination	1	13.8×	0.079	MED12
positive regulation of DNA-templated transcription	1	9.3×	0.109	MED12
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	MED12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MED12	1	2
CXorf65	0	0
GJB1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6
GJB1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	MED12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CXorf65, GJB1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CXorf65	0	—
GJB1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.