Osteopathia striata with cranial sclerosis

Summary

Osteopathia striata with cranial sclerosis (MONDO:0010310) is a disease caused by AMER1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AMER1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 60
• Phenotypes (HPO): 44

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0002684	Thickened calvaria	Very frequent (80-99%)
HP:0005465	Facial hyperostosis	Very frequent (80-99%)
HP:0008808	High iliac wings	Very frequent (80-99%)
HP:0008818	Large iliac wings	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0011002	Osteopetrosis	Very frequent (80-99%)
HP:0100670	Rough bone trabeculation	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000176	Submucous cleft hard palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000239	Large fontanelles	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0005469	Flat occiput	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001555	Asymmetry of the thorax	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001680	Coarctation of aorta	Occasional (5-29%)
HP:0002300	Mutism	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0003298	Spina bifida occulta	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003510	Severe short stature	Occasional (5-29%)
HP:0010529	Echolalia	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0012368	Flat face	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	osteopathia striata with cranial sclerosis
Mondo ID	MONDO:0010310
MeSH	C536053
OMIM	300373
Orphanet	2780
DOID	DOID:0060886
SNOMED CT	254129003
UMLS	C0432268
MedGen	96590
GARD	0004148
Is cancer (heuristic)	no

Also known as: hyperostosis generalisata with striations · OSCS · osteopathia striata - cranial sclerosis · osteopathia striata cranial sclerosis · osteopathia striata with cranial sclerosis · Osteopathia striata with cranial sclerosis, X-linked dominant · Robinow-Unger syndrome

Data availability: 60 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteopetrosis › osteopathia striata with cranial sclerosis

Related subtypes (10): melorheostosis, osteomesopyknosis, dysosteosclerosis, pycnodysostosis, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, infantile osteopetrosis with neuroaxonal dysplasia, osteosclerotic metaphyseal dysplasia, autosomal recessive osteopetrosis, autosomal dominant osteopetrosis, early-onset calcifying leukoencephalopathy-skeletal dysplasia

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

60 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 19 pathogenic, 6 benign/likely benign, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10704	NM_152424.4(AMER1):c.671del (p.Pro224fs)	AMER1	Pathogenic	no assertion criteria provided
10705	NM_152424.4(AMER1):c.780dup (p.Pro261fs)	AMER1	Pathogenic	criteria provided, single submitter
10707	NM_152424.4(AMER1):c.1057C>T (p.Arg353Ter)	AMER1	Pathogenic	criteria provided, multiple submitters, no conflicts
10708	NM_152424.4(AMER1):c.1072C>T (p.Arg358Ter)	AMER1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323110	NM_152424.4(AMER1):c.179_180del (p.Phe60fs)	AMER1	Pathogenic	criteria provided, single submitter
1323114	NM_152424.4(AMER1):c.1000G>T (p.Glu334Ter)	AMER1	Pathogenic	criteria provided, single submitter
29979	NM_152424.4(AMER1):c.429T>A (p.Cys143Ter)	AMER1	Pathogenic	no assertion criteria provided
3062083	NM_152424.4(AMER1):c.877del (p.Lys292_Val293insTer)	AMER1	Pathogenic	criteria provided, single submitter
3377319	NM_152424.4(AMER1):c.694del (p.Gln232fs)	AMER1	Pathogenic	criteria provided, multiple submitters, no conflicts
37045	NM_152424.4(AMER1):c.1267del (p.Leu423fs)	AMER1	Pathogenic	no assertion criteria provided
37046	NM_152424.4(AMER1):c.811C>T (p.Gln271Ter)	AMER1	Pathogenic	no assertion criteria provided
4813475	NM_152424.4(AMER1):c.310del (p.His104fs)	AMER1	Pathogenic	criteria provided, single submitter
636242	NM_152424.4(AMER1):c.565C>T (p.Gln189Ter)	AMER1	Pathogenic	criteria provided, multiple submitters, no conflicts
862773	NM_152424.4(AMER1):c.1489C>T (p.Arg497Ter)	AMER1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974942	NC_000023.11:g.(64175170_64275169)del	AMER1	Pathogenic	criteria provided, single submitter
974943	NC_000023.11:g.63635938_64279758del	AMER1	Pathogenic	criteria provided, single submitter
974944	NM_152424.4(AMER1):c.555_556del (p.Gly186_Ala187insTer)	AMER1	Pathogenic	criteria provided, single submitter
975791	NC_000023.11:g.64205190_64206761del	AMER1	Pathogenic	criteria provided, single submitter
10706	NC_000023.11:g.(57537466_63428182)_(65235775_65512709)del	LOC130068356	Pathogenic	no assertion criteria provided
975790	NC_000023.11:g.64203965_64205889del	LOC130068367	Pathogenic	criteria provided, single submitter
2572435	NM_152424.4(AMER1):c.1104_1105dup (p.Gly369fs)	AMER1	Likely pathogenic	criteria provided, single submitter
2671923	NM_152424.4(AMER1):c.1575_1590del (p.Tyr526fs)	AMER1	Likely pathogenic	criteria provided, single submitter
3235193	NM_152424.4(AMER1):c.871G>T (p.Glu291Ter)	AMER1	Likely pathogenic	criteria provided, single submitter
3775971	NM_152424.4(AMER1):c.1756C>T (p.Arg586Ter)	AMER1	Likely pathogenic	criteria provided, single submitter
438746	NM_152424.4(AMER1):c.655del (p.Glu219fs)	AMER1	Likely pathogenic	no assertion criteria provided
804016	NM_152424.4(AMER1):c.1384del (p.Glu462fs)	AMER1	Likely pathogenic	criteria provided, single submitter
133501	NM_152424.4(AMER1):c.85G>A (p.Ala29Thr)	AMER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476163	NM_152424.4(AMER1):c.2884G>A (p.Ala962Thr)	AMER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691269	NM_152424.4(AMER1):c.3130A>G (p.Met1044Val)	AMER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2990981	NM_152424.4(AMER1):c.1900C>T (p.Arg634Cys)	AMER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
AMER1	Definitive	X-linked	osteopathia striata with cranial sclerosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMER1	Orphanet:2780	Osteopathia striata-cranial sclerosis syndrome

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
AMER1	HGNC:26837	ENSG00000184675	Q5JTC6	APC membrane recruitment protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMER1	APC membrane recruitment protein 1	Regulator of the canonical Wnt signaling pathway.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMER1	Other/Unknown	no		AMER

Expression context

Cohort genes with no expression data: 0.

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
cortical plate	1
myocardium	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMER1	156	ubiquitous	yes	cortical plate, skeletal muscle tissue of rectus abdominis, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMER1	1,026

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMER1	Q5JTC6	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Deletions in the AMER1 gene destabilize the destruction complex	1	11420.0×	0.003	AMER1
Signaling by AXIN mutants	1	1038.2×	0.003	AMER1
Signaling by CTNNB1 phospho-site mutants	1	1038.2×	0.003	AMER1
Signaling by APC mutants	1	1038.2×	0.003	AMER1
Signaling by AMER1 mutants	1	1038.2×	0.003	AMER1
APC truncation mutants have impaired AXIN binding	1	815.7×	0.003	AMER1
AXIN missense mutants destabilize the destruction complex	1	815.7×	0.003	AMER1
Truncations of AMER1 destabilize the destruction complex	1	815.7×	0.003	AMER1
Signaling by GSK3beta mutants	1	761.3×	0.003	AMER1
CTNNB1 S33 mutants aren’t phosphorylated	1	761.3×	0.003	AMER1
CTNNB1 S37 mutants aren’t phosphorylated	1	761.3×	0.003	AMER1
CTNNB1 S45 mutants aren’t phosphorylated	1	761.3×	0.003	AMER1
CTNNB1 T41 mutants aren’t phosphorylated	1	761.3×	0.003	AMER1
Beta-catenin phosphorylation cascade	1	671.8×	0.003	AMER1
Signaling by WNT in cancer	1	601.0×	0.003	AMER1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	356.9×	0.005	AMER1
Degradation of beta-catenin by the destruction complex	1	173.0×	0.010	AMER1
Cellular response to chemical stress	1	142.8×	0.011	AMER1
KEAP1-NFE2L2 pathway	1	120.2×	0.012	AMER1
TCF dependent signaling in response to WNT	1	117.7×	0.012	AMER1
Signaling by WNT	1	112.0×	0.012	AMER1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	AMER1
Neddylation	1	47.4×	0.027	AMER1
Cellular responses to stress	1	36.8×	0.033	AMER1
Cellular responses to stimuli	1	31.5×	0.037	AMER1
Post-translational protein modification	1	19.2×	0.058	AMER1
Disease	1	13.1×	0.082	AMER1
Metabolism of proteins	1	12.4×	0.084	AMER1
Signal Transduction	1	10.2×	0.098	AMER1

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
mesenchymal cell differentiation involved in kidney development	1	8426.0×	0.001	AMER1
regulation of canonical Wnt signaling pathway	1	543.6×	0.007	AMER1
adipose tissue development	1	401.2×	0.007	AMER1
bone development	1	276.3×	0.007	AMER1
positive regulation of protein ubiquitination	1	213.3×	0.007	AMER1
positive regulation of protein catabolic process	1	203.0×	0.007	AMER1
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.008	AMER1
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.010	AMER1
Wnt signaling pathway	1	99.7×	0.010	AMER1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AMER1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AMER1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMER1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.