Calvarial doughnut lesions-bone fragility syndrome

Summary

Calvarial doughnut lesions-bone fragility syndrome (MONDO:0007470) is a disease caused by SGMS2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SGMS2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	calvarial doughnut lesions-bone fragility syndrome
Mondo ID	MONDO:0007470
MeSH	C565089
OMIM	126550
Orphanet	85192
DOID	DOID:0080721
SNOMED CT	720598005
UMLS	C1852022
MedGen	377572
GARD	0016739
Is cancer (heuristic)	no

Also known as: calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia · familial doughnut lesions of skull

Data availability: 7 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › calvarial doughnut lesions-bone fragility syndrome

Related subtypes (32): Cole-Carpenter syndrome 1, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, short stature-optic atrophy-Pelger-Huët anomaly syndrome, osteogenesis imperfecta type 14, osteogenesis imperfecta type 15, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18, osteogenesis imperfecta, type 19

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

7 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
635285	NM_001375905.1(SGMS2):c.148C>T (p.Arg50Ter)	CYP2U1-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2171606	NM_001375905.1(SGMS2):c.714_715insAT (p.Phe239fs)	CYP2U1-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2412781	NM_001375905.1(SGMS2):c.641T>C (p.Ile214Thr)	CYP2U1-AS1	Uncertain significance	criteria provided, single submitter
3898031	NM_001375905.1(SGMS2):c.899T>G (p.Leu300Trp)	CYP2U1-AS1	Uncertain significance	criteria provided, single submitter
1421768	NM_001375905.1(SGMS2):c.737G>A (p.Arg246His)	SGMS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4080043	NM_001375905.1(SGMS2):c.629del (p.Gly210fs)	SGMS2	Uncertain significance	criteria provided, single submitter
1595949	NM_001375905.1(SGMS2):c.171G>A (p.Pro57=)	CYP2U1-AS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
SGMS2	Strong	Autosomal dominant	calvarial doughnut lesions-bone fragility syndrome	3

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SGMS2	HGNC:28395	ENSG00000164023	Q8NHU3	Phosphatidylcholine:ceramide cholinephosphotransferase 2	gencc,clinvar
CYP2U1-AS1	HGNC:54817	ENSG00000245293		CYP2U1 and SGMS2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SGMS2	Phosphatidylcholine:ceramide cholinephosphotransferase 2	Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SGMS2	Enzyme (other)	yes	2.7.8.27	Sphingomyelin_synth-like_dom, Sphingomyelin_synth-like
CYP2U1-AS1	Other/Unknown	no

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
epithelial cell of pancreas	1
secondary oocyte	1
tibia	1
C1 segment of cervical spinal cord	1
corpus callosum	1
substantia nigra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SGMS2	233	ubiquitous	marker	tibia, secondary oocyte, epithelial cell of pancreas
CYP2U1-AS1	133	broad	marker	C1 segment of cervical spinal cord, corpus callosum, substantia nigra

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SGMS2	634
CYP2U1-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SGMS2	Q8NHU3	77.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Sphingolipid de novo biosynthesis	1	285.5×	0.012	SGMS2
Sphingolipid metabolism	1	167.9×	0.012	SGMS2
Metabolism of lipids	1	31.6×	0.042	SGMS2
Metabolism	1	11.6×	0.086	SGMS2

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
ceramide phosphoethanolamine biosynthetic process	1	16852.0×	3e-04	SGMS2
sphingomyelin biosynthetic process	1	1404.3×	0.002	SGMS2
regulation of bone mineralization	1	732.7×	0.002	SGMS2
ceramide biosynthetic process	1	421.3×	0.003	SGMS2
sphingolipid biosynthetic process	1	358.6×	0.003	SGMS2

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
SGMS2	0	0
CYP2U1-AS1	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
SGMS2	30	Binding:30

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SGMS2	2.7.8.27	sphingomyelin synthase

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	1	SGMS2
E	Difficult family or no structure, no drug	1	CYP2U1-AS1

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)
SGMS2	30	—
CYP2U1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.