familial scaphocephaly syndrome, McGillivray type

Summary

familial scaphocephaly syndrome, McGillivray type (MONDO:0012307) is a disease caused by FGFR2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FGFR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 116
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0010807	Open bite	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0010059	Broad hallux phalanx	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial scaphocephaly syndrome, McGillivray type
Mondo ID	MONDO:0012307
MeSH	C566511
OMIM	609579
Orphanet	168624
ICD-11	512057922
UMLS	C1865070
MedGen	355365
GARD	0003426
Is cancer (heuristic)	no

Also known as: scaphocephaly, maxillary retrusion, and mental retardation · scaphocephaly-macrocephaly-maxillary retrusion-intellectual disability syndrome

Data availability: 116 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › familial scaphocephaly syndrome › familial scaphocephaly syndrome, McGillivray type

Related subtypes (1): craniosynostosis-Dandy-Walker malformation-hydrocephalus 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

116 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 17 conflicting classifications of pathogenicity, 14 likely benign, 7 pathogenic/likely pathogenic, 6 pathogenic, 4 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13263	NM_000141.5(FGFR2):c.1025G>A (p.Cys342Tyr)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13268	NM_000141.5(FGFR2):c.1032G>A (p.Ala344=)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13272	NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13273	NM_000141.5(FGFR2):c.758C>G (p.Pro253Arg)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13277	NM_000141.5(FGFR2):c.1124A>G (p.Tyr375Cys)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13289	NM_000141.5(FGFR2):c.943G>T (p.Ala315Ser)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13293	NM_000141.5(FGFR2):c.870G>T (p.Trp290Cys)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
13295	NM_000141.5(FGFR2):c.1576A>G (p.Lys526Glu)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13296	NM_000141.5(FGFR2):c.1942G>A (p.Ala648Thr)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
374817	NM_000141.5(FGFR2):c.1013G>A (p.Gly338Glu)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374823	NM_000141.5(FGFR2):c.1694A>G (p.Glu565Gly)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449024	NM_000141.5(FGFR2):c.314A>G (p.Tyr105Cys)	FGFR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
478046	NM_000141.5(FGFR2):c.1150G>A (p.Gly384Arg)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1000813	NM_000141.5(FGFR2):c.16C>T (p.Arg6Cys)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1052478	NM_000141.5(FGFR2):c.1348C>T (p.Arg450Cys)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134387	NM_000141.5(FGFR2):c.34G>A (p.Val12Met)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1415015	NM_000141.5(FGFR2):c.2426T>C (p.Leu809Pro)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1503438	NM_000141.5(FGFR2):c.287G>T (p.Gly96Val)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2891853	NM_000141.5(FGFR2):c.1029G>A (p.Leu343=)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2977031	NM_000141.5(FGFR2):c.963C>A (p.Asp321Glu)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298998	NM_000141.5(FGFR2):c.1774C>T (p.Arg592Cys)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3064171	NM_000141.5(FGFR2):c.943G>A (p.Ala315Thr)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3075688	NM_000141.5(FGFR2):c.1124A>T (p.Tyr375Phe)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3591007	NM_000141.5(FGFR2):c.556A>G (p.Met186Val)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3591089	NM_000141.5(FGFR2):c.151G>A (p.Val51Met)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374808	NM_000141.5(FGFR2):c.138A>C (p.Gln46His)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374814	NM_000141.5(FGFR2):c.940-2A>G	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497484	NM_000141.5(FGFR2):c.289G>A (p.Ala97Thr)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
577711	NM_000141.5(FGFR2):c.989G>A (p.Arg330Gln)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877638	NM_000141.5(FGFR2):c.1213A>G (p.Lys405Glu)	FGFR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 38 · Orphanet: 12 · 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
FGFR2	Strong	Autosomal dominant	familial scaphocephaly syndrome, McGillivray type	38

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
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
FGFR2	449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR2	P21802	63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 1 evidence-associated genes (1 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 1 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	11420.0×	8e-04	FGFR2
Signaling by FGFR2 fusions	1	11420.0×	8e-04	FGFR2
FGFR2b ligand binding and activation	1	1142.0×	0.004	FGFR2
FGFR2c ligand binding and activation	1	878.5×	0.004	FGFR2
Activated point mutants of FGFR2	1	671.8×	0.004	FGFR2
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.004	FGFR2
Signaling by FGFR2 IIIa TM	1	601.0×	0.004	FGFR2
PI-3K cascade:FGFR2	1	496.5×	0.004	FGFR2
SHC-mediated cascade:FGFR2	1	475.8×	0.004	FGFR2
FRS-mediated FGFR2 signaling	1	439.2×	0.004	FGFR2
FGFR2 alternative splicing	1	423.0×	0.004	FGFR2
Negative regulation of FGFR2 signaling	1	368.4×	0.004	FGFR2
PI3K Cascade	1	271.9×	0.005	FGFR2
Signaling by FGFR2 in disease	1	265.6×	0.005	FGFR2
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	FGFR2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	FGFR2
PIP3 activates AKT signaling	1	66.8×	0.016	FGFR2
RAF/MAP kinase cascade	1	61.1×	0.016	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell	1	16852.0×	0.001	FGFR2
fibroblast growth factor receptor signaling pathway involved in hemopoiesis	1	16852.0×	0.001	FGFR2
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow	1	16852.0×	0.001	FGFR2
lateral sprouting from an epithelium	1	16852.0×	0.001	FGFR2
orbitofrontal cortex development	1	8426.0×	0.001	FGFR2
prostate gland morphogenesis	1	8426.0×	0.001	FGFR2
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development	1	8426.0×	0.001	FGFR2
mammary gland bud formation	1	8426.0×	0.001	FGFR2
branch elongation involved in salivary gland morphogenesis	1	8426.0×	0.001	FGFR2
mesenchymal cell differentiation involved in lung development	1	8426.0×	0.001	FGFR2
regulation of osteoblast proliferation	1	5617.3×	0.001	FGFR2
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	5617.3×	0.001	FGFR2
prostate epithelial cord elongation	1	5617.3×	0.001	FGFR2
ventricular zone neuroblast division	1	4213.0×	0.001	FGFR2
embryonic organ morphogenesis	1	4213.0×	0.001	FGFR2
reproductive structure development	1	4213.0×	0.001	FGFR2
regulation of morphogenesis of a branching structure	1	4213.0×	0.001	FGFR2
positive regulation of phospholipase activity	1	3370.4×	0.001	FGFR2
regulation of smooth muscle cell differentiation	1	3370.4×	0.001	FGFR2
branching involved in prostate gland morphogenesis	1	3370.4×	0.001	FGFR2
epithelial cell proliferation involved in salivary gland morphogenesis	1	3370.4×	0.001	FGFR2
mesenchymal cell proliferation involved in lung development	1	3370.4×	0.001	FGFR2
epidermis morphogenesis	1	2808.7×	0.001	FGFR2
gland morphogenesis	1	2407.4×	0.001	FGFR2
branching morphogenesis of a nerve	1	2407.4×	0.001	FGFR2
bud elongation involved in lung branching	1	2407.4×	0.001	FGFR2
positive regulation of epithelial cell proliferation involved in lung morphogenesis	1	2407.4×	0.001	FGFR2
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	2407.4×	0.001	FGFR2
pyramidal neuron development	1	2106.5×	0.001	FGFR2
otic vesicle formation	1	2106.5×	0.001	FGFR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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): 1.

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
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: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.