Meier-Gorlin syndrome 1

Summary

Meier-Gorlin syndrome 1 (MONDO:0009143) is a disease caused by ORC1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: ORC1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 87

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meier-Gorlin syndrome 1
Mondo ID	MONDO:0009143
OMIM	224690
DOID	DOID:0080512
SNOMED CT	703508009
UMLS	C4552001
MedGen	1641240
GARD	0015162
Is cancer (heuristic)	no

Also known as: Meier-Gorlin syndrome 1 · Meier-Gorlin syndrome caused by mutation in ORC1 · Meier-Gorlin syndrome type 1 · MGORS1 · ORC1 Meier-Gorlin syndrome

Data availability: 87 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meier-Gorlin syndrome › Meier-Gorlin syndrome 1

Related subtypes (9): Meier-Gorlin syndrome 2, Meier-Gorlin syndrome 3, Meier-Gorlin syndrome 4, Meier-Gorlin syndrome 5, Meier-Gorlin syndrome 6, Meier-Gorlin syndrome 7, Meier-Gorlin syndrome 8, Meier-Gorlin syndrome 9, Meier-Gorlin syndrome 10

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

87 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 16 conflicting classifications of pathogenicity, 9 pathogenic, 9 benign/likely benign, 8 benign, 6 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1177300	NM_017613.4(DONSON):c.48del (p.Glu17fs)	DONSON	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13271	NM_000141.5(FGFR2):c.1040C>G (p.Ser347Cys)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034052	NM_004153.4(ORC1):c.237del (p.Pro80fs)	ORC1	Pathogenic	criteria provided, single submitter
1173052	NM_004153.4(ORC1):c.1865T>C (p.Leu622Pro)	ORC1	Pathogenic	criteria provided, single submitter
1173067	NC_000001.11:g.52369378_52373625del	ORC1	Pathogenic	criteria provided, single submitter
1173068	NM_004153.4(ORC1):c.217G>A (p.Glu73Lys)	ORC1	Pathogenic	criteria provided, single submitter
1323388	NM_004153.4(ORC1):c.403-2A>C	ORC1	Pathogenic	criteria provided, single submitter
2873337	NM_004153.4(ORC1):c.2193_2194del (p.Glu731fs)	ORC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2969104	NM_004153.4(ORC1):c.961C>T (p.Arg321Ter)	ORC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30230	NM_004153.4(ORC1):c.380A>G (p.Glu127Gly)	ORC1	Pathogenic	no assertion criteria provided
30232	NM_004153.4(ORC1):c.314G>A (p.Arg105Gln)	ORC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30234	NM_004153.4(ORC1):c.1999_2000delinsA (p.Val667fs)	ORC1	Pathogenic	no assertion criteria provided
30235	NM_004153.4(ORC1):c.1482-2A>G	ORC1	Pathogenic	no assertion criteria provided
998022	NM_004153.4(ORC1):c.[2483C>T;2484del]		Likely pathogenic	no assertion criteria provided
2441664	NM_004153.4(ORC1):c.688dup (p.Thr230fs)	ORC1	Likely pathogenic	criteria provided, single submitter
30233	NM_004153.4(ORC1):c.2159G>A (p.Arg720Gln)	ORC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780064	NM_004153.4(ORC1):c.1145del (p.Lys382fs)	ORC1	Likely pathogenic	criteria provided, single submitter
4056696	NM_004153.4(ORC1):c.2209del (p.Gln737fs)	ORC1	Likely pathogenic	criteria provided, single submitter
982308	NM_004153.4(ORC1):c.313C>T (p.Arg105Trp)	ORC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
129852	NM_004153.4(ORC1):c.1581A>G (p.Gly527=)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211798	NM_004153.4(ORC1):c.1318T>C (p.Ser440Pro)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211801	NM_004153.4(ORC1):c.403-7A>C	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297578	NM_004153.4(ORC1):c.2382G>A (p.Thr794=)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297580	NM_004153.4(ORC1):c.1819A>G (p.Thr607Ala)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297581	NM_004153.4(ORC1):c.1671C>T (p.Ala557=)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297589	NM_004153.4(ORC1):c.387C>T (p.Ile129=)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30231	NM_004153.4(ORC1):c.266T>C (p.Phe89Ser)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30236	NM_004153.4(ORC1):c.1996C>T (p.Arg666Trp)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436115	NM_004153.4(ORC1):c.608C>T (p.Thr203Ile)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702027	NM_004153.4(ORC1):c.2162G>A (p.Arg721Gln)	ORC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 16 · 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
ORC1	Definitive	Autosomal recessive	Meier-Gorlin syndrome 1	5
SLC25A15	Definitive	Autosomal recessive	Meier-Gorlin syndrome 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A15	Orphanet:415	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
ORC1	Orphanet:2554	Ear-patella-short stature syndrome
DONSON	Orphanet:572768	Microcephaly-micromelia syndrome
DONSON	Orphanet:572773	Microcephaly-short stature-limb abnormalities syndrome
FGFR2	Orphanet:1540	Jackson-Weiss syndrome
FGFR2	Orphanet:1555	Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome
FGFR2	Orphanet:168624	Familial scaphocephaly syndrome, McGillivray type
FGFR2	Orphanet:207	Crouzon syndrome
FGFR2	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR2	Orphanet:313855	FGFR2-related bent bone dysplasia
FGFR2	Orphanet:596008	Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis
FGFR2	Orphanet:794	Saethre-Chotzen syndrome
FGFR2	Orphanet:87	Apert syndrome
FGFR2	Orphanet:93258	Pfeiffer syndrome type 1
FGFR2	Orphanet:93259	Pfeiffer syndrome type 2
FGFR2	Orphanet:93260	Pfeiffer syndrome type 3

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A15	HGNC:10985	ENSG00000102743	Q9Y619	Mitochondrial ornithine transporter 1	gencc,clinvar
ORC1	HGNC:8487	ENSG00000085840	Q13415	Origin recognition complex subunit 1	gencc,clinvar
DONSON	HGNC:2993	ENSG00000159147	Q9NYP3	Protein downstream neighbor of Son	clinvar
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A15	Mitochondrial ornithine transporter 1	Mitochondrial ornithine-citrulline antiporter.
ORC1	Origin recognition complex subunit 1	Component of the origin recognition complex (ORC) that binds origins of replication.
DONSON	Protein downstream neighbor of Son	Replisome component that maintains genome stability by protecting stalled or damaged replication forks.
FGFR2	Fibroblast growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic de…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Kinase	1	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A15	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mitochondrial_Carrier
ORC1	Enzyme (other)	yes	3.6.4.B8	BAH_dom, AAA+_ATPase, ATPase_AAA_core
DONSON	Other/Unknown	no		Donson
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
duodenum	1
liver	1
right lobe of liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
left testis	1
right testis	1
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A15	198	ubiquitous	marker	liver, right lobe of liver, duodenum
ORC1	152	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, primordial germ cell in gonad
DONSON	247	ubiquitous	marker	ventricular zone, right testis, left testis
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ORC1	2,879
DONSON	1,477
SLC25A15	874
FGFR2	449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR2	P21802	63
ORC1	Q13415	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A15	Q9Y619	87.43
DONSON	Q9NYP3	72.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by FGFR2 amplification mutants	1	3806.7×	0.004	FGFR2
Signaling by FGFR2 fusions	1	3806.7×	0.004	FGFR2
SLC25A15 variants cause hyperornithinemia-hyperammonemia-homocitrullinemia syndrome	1	1903.3×	0.005	SLC25A15
CDC6 association with the ORC:origin complex	1	475.8×	0.012	ORC1
E2F-enabled inhibition of pre-replication complex formation	1	423.0×	0.012	ORC1
FGFR2b ligand binding and activation	1	380.7×	0.012	FGFR2
FGFR2c ligand binding and activation	1	292.8×	0.012	FGFR2
Urea cycle	1	292.8×	0.012	SLC25A15
Activated point mutants of FGFR2	1	223.9×	0.013	FGFR2
Phospholipase C-mediated cascade; FGFR2	1	211.5×	0.013	FGFR2
Signaling by FGFR2 IIIa TM	1	200.3×	0.013	FGFR2
PI-3K cascade:FGFR2	1	165.5×	0.013	FGFR2
SHC-mediated cascade:FGFR2	1	158.6×	0.013	FGFR2
FRS-mediated FGFR2 signaling	1	146.4×	0.013	FGFR2
FGFR2 alternative splicing	1	141.0×	0.013	FGFR2
Negative regulation of FGFR2 signaling	1	122.8×	0.014	FGFR2
G1/S-Specific Transcription	1	119.0×	0.014	ORC1
Activation of the pre-replicative complex	1	108.8×	0.014	ORC1
Activation of ATR in response to replication stress	1	100.2×	0.015	ORC1
PI3K Cascade	1	90.6×	0.015	FGFR2
Signaling by FGFR2 in disease	1	88.5×	0.015	FGFR2
Orc1 removal from chromatin	1	59.5×	0.021	ORC1
Assembly of the ORC complex at the origin of replication	1	55.2×	0.022	ORC1
Assembly of the pre-replicative complex	1	46.4×	0.025	ORC1
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.026	FGFR2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.033	FGFR2
PIP3 activates AKT signaling	1	22.3×	0.046	FGFR2
RAF/MAP kinase cascade	1	20.4×	0.048	FGFR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitotic DNA replication checkpoint signaling	2	766.0×	2e-04	ORC1, DONSON
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell	1	4213.0×	0.005	FGFR2
fibroblast growth factor receptor signaling pathway involved in hemopoiesis	1	4213.0×	0.005	FGFR2
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow	1	4213.0×	0.005	FGFR2
lateral sprouting from an epithelium	1	4213.0×	0.005	FGFR2
orbitofrontal cortex development	1	2106.5×	0.005	FGFR2
prostate gland morphogenesis	1	2106.5×	0.005	FGFR2
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development	1	2106.5×	0.005	FGFR2
mammary gland bud formation	1	2106.5×	0.005	FGFR2
branch elongation involved in salivary gland morphogenesis	1	2106.5×	0.005	FGFR2
mesenchymal cell differentiation involved in lung development	1	2106.5×	0.005	FGFR2
nuclear DNA replication	1	1404.3×	0.005	DONSON
regulation of osteoblast proliferation	1	1404.3×	0.005	FGFR2
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	1404.3×	0.005	FGFR2
prostate epithelial cord elongation	1	1404.3×	0.005	FGFR2
ventricular zone neuroblast division	1	1053.2×	0.005	FGFR2
embryonic organ morphogenesis	1	1053.2×	0.005	FGFR2
reproductive structure development	1	1053.2×	0.005	FGFR2
regulation of morphogenesis of a branching structure	1	1053.2×	0.005	FGFR2
mitochondrial L-ornithine transmembrane transport	1	1053.2×	0.005	SLC25A15
positive regulation of phospholipase activity	1	842.6×	0.005	FGFR2
regulation of smooth muscle cell differentiation	1	842.6×	0.005	FGFR2
branching involved in prostate gland morphogenesis	1	842.6×	0.005	FGFR2
epithelial cell proliferation involved in salivary gland morphogenesis	1	842.6×	0.005	FGFR2
mesenchymal cell proliferation involved in lung development	1	842.6×	0.005	FGFR2
epidermis morphogenesis	1	702.2×	0.005	FGFR2
L-lysine transmembrane transport	1	702.2×	0.005	SLC25A15
gland morphogenesis	1	601.9×	0.005	FGFR2
branching morphogenesis of a nerve	1	601.9×	0.005	FGFR2
bud elongation involved in lung branching	1	601.9×	0.005	FGFR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
FGFR2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR2	59	4
SLC25A15	0	0
ORC1	0	0
DONSON	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
LINIFANIB	3	FGFR2
SEMAXANIB	3	FGFR2
BRIVANIB	3	FGFR2
CEDIRANIB	3	FGFR2
DOVITINIB	3	FGFR2
LESTAURTINIB	3	FGFR2
TANDUTINIB	2	FGFR2
DORAMAPIMOD	2	FGFR2
FORETINIB	2	FGFR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR2	966	Binding:940, Functional:22, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ORC1	3.6.4.B8
FGFR2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FGFR2	966

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
LINIFANIB	3	FGFR2
SEMAXANIB	3	FGFR2
BRIVANIB	3	FGFR2
CEDIRANIB	3	FGFR2
DOVITINIB	3	FGFR2
LESTAURTINIB	3	FGFR2
TANDUTINIB	2	FGFR2
DORAMAPIMOD	2	FGFR2
FORETINIB	2	FGFR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ORC1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC25A15, DONSON

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A15	0	—
ORC1	0	—
DONSON	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.