Hunter-McAlpine craniosynostosis

Summary

Hunter-McAlpine craniosynostosis (MONDO:0011065) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Hunter-McAlpine craniosynostosis
Mondo ID	MONDO:0011065
MeSH	C536072
OMIM	601379
Orphanet	97340
ICD-11	1445975694
SNOMED CT	721227001
UMLS	C1832408
MedGen	321949
GARD	0002754
Is cancer (heuristic)	no

Also known as: craniosynostosis, mental deficiency, almond-shaped palpebral fissures, downturned mouth, mild acral-skeletal anomalies, and short stature · Hunter-McAlpine syndrome

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › Hunter-McAlpine craniosynostosis

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, Baller-Gerold syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, lethal occipital encephalocele-skeletal dysplasia syndrome, TCF12-related craniosynostosis, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703528	GRCh37/hg19 5q32-35.3(chr5:149010383-180719789)	HK3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HOOK3	HGNC:23576	ENSG00000168172	Q86VS8	Protein Hook homolog 3	clinvar
HK3	HGNC:4925	ENSG00000160883	P52790	Hexokinase-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HOOK3	Protein Hook homolog 3	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
HK3	Hexokinase-3	Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOOK3	Other/Unknown	no		CH_dom, Hook_C, CH_dom_sf
HK3	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
sural nerve	1
tendon	1
granulocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HOOK3	257	ubiquitous	marker	calcaneal tendon, sural nerve, tendon
HK3	176	broad	marker	monocyte, granulocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HOOK3	2,350
HK3	1,996

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HOOK3	Q86VS8	5
HK3	P52790	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Glycolysis	1	285.5×	0.007	HK3
Neutrophil degranulation	1	23.1×	0.043	HK3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
interkinetic nuclear migration	1	1685.2×	0.005	HOOK3
Golgi localization	1	1053.2×	0.005	HOOK3
microtubule anchoring at centrosome	1	702.2×	0.005	HOOK3
protein localization to perinuclear region of cytoplasm	1	702.2×	0.005	HOOK3
glucose 6-phosphate metabolic process	1	648.1×	0.005	HK3
fructose 6-phosphate metabolic process	1	561.7×	0.005	HK3
cytoskeleton-dependent intracellular transport	1	468.1×	0.005	HOOK3
canonical glycolysis	1	351.1×	0.005	HK3
protein localization to centrosome	1	337.0×	0.005	HOOK3
neuronal stem cell population maintenance	1	337.0×	0.005	HOOK3
early endosome to late endosome transport	1	324.1×	0.005	HOOK3
negative regulation of neurogenesis	1	312.1×	0.005	HOOK3
intracellular glucose homeostasis	1	290.6×	0.005	HK3
glycolytic process	1	191.5×	0.007	HK3
endosome organization	1	187.2×	0.007	HOOK3
cytoplasmic microtubule organization	1	172.0×	0.007	HOOK3
endosome to lysosome transport	1	168.5×	0.007	HOOK3
lysosome organization	1	153.2×	0.007	HOOK3
glucose metabolic process	1	127.7×	0.008	HK3
protein transport	1	21.9×	0.045	HOOK3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HOOK3	0	0
HK3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HK3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HK3	2.7.1.1	hexokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	1	HK3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HOOK3

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)
HOOK3	0	—
HK3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.