Regressive spondylometaphyseal dysplasia

Summary

Regressive spondylometaphyseal dysplasia (MONDO:0018663) is a disease caused by LBR (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LBR (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	regressive spondylometaphyseal dysplasia
Mondo ID	MONDO:0018663
OMIM	618019
Orphanet	448267
UMLS	C4747922
MedGen	1648288
GARD	0017782
Is cancer (heuristic)	no

Also known as: Pelger-Huet anomaly with mild skeletal anomalies · regressive spondylometaphyseal dysplasia

Data availability: 16 ClinVar variants · 3 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 › spondylometaphyseal dysplasia › regressive spondylometaphyseal dysplasia

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, spondylometaphyseal dysplasia, Sedaghatian type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia-cone-rod dystrophy syndrome, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, autosomal recessive spondylometaphyseal dysplasia, Megarbane type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal 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

16 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
224875	NM_002296.4(LBR):c.1640A>G (p.Asn547Ser)	LBR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424332	NM_002296.4(LBR):c.1535G>A (p.Arg512Gln)	LBR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545626	NM_002296.4(LBR):c.1757G>A (p.Arg586His)	LBR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
426800	NM_002296.4(LBR):c.1366C>G (p.Leu456Val)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
748574	NM_002296.4(LBR):c.271C>T (p.Pro91Ser)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9533	NM_002296.4(LBR):c.1114C>T (p.Arg372Cys)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1414465	NM_002296.4(LBR):c.860T>C (p.Ile287Thr)	LBR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1433684	NM_002296.4(LBR):c.261_262inv (p.Gly88Ser)	LBR	Uncertain significance	criteria provided, single submitter
2902022	NM_002296.4(LBR):c.505C>T (p.Arg169Cys)	LBR	Uncertain significance	criteria provided, multiple submitters, no conflicts
295931	NM_002296.4(LBR):c.1590G>A (p.Thr530=)	LBR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3672644	NM_002296.4(LBR):c.1097A>G (p.Tyr366Cys)	LBR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779811	NM_002296.4(LBR):c.893-2dup	LBR	Uncertain significance	criteria provided, single submitter
3891566	NM_002296.4(LBR):c.1486T>G (p.Cys496Gly)	LBR	Uncertain significance	criteria provided, single submitter
874222	NM_002296.4(LBR):c.1034A>G (p.Tyr345Cys)	LBR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1620500	NM_002296.4(LBR):c.1315-13T>C	LBR	Likely benign	criteria provided, multiple submitters, no conflicts
295940	NM_002296.4(LBR):c.843A>G (p.Val281=)	LBR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
LBR	Definitive	Autosomal recessive	Greenberg dysplasia	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LBR	Orphanet:1426	Greenberg dysplasia
LBR	Orphanet:448267	Regressive spondylometaphyseal dysplasia
LBR	Orphanet:779	Reynolds 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
LBR	HGNC:6518	ENSG00000143815	Q14739	Delta(14)-sterol reductase LBR	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LBR	Delta(14)-sterol reductase LBR	Catalyzes the reduction of the C14-unsaturated bond of lanosterol, as part of the metabolic pathway leading to cholesterol biosynthesis.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LBR	Enzyme (other)	yes	1.3.1.70	ERG24_DHCR-like, Tudor, Sterol_reductase_CS

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
bone marrow	1
thymus	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LBR	294	ubiquitous	marker	trabecular bone tissue, bone marrow, thymus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LBR	2,789

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LBR	Q14739	1

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
Cholesterol biosynthesis	1	1142.0×	0.013	LBR
Cholesterol biosynthesis via desmosterol (Bloch pathway)	1	1142.0×	0.013	LBR
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.016	LBR
Regulation of MECP2 expression and activity	1	368.4×	0.017	LBR
Transcriptional Regulation by MECP2	1	317.2×	0.017	LBR
Nuclear Envelope (NE) Reassembly	1	292.8×	0.017	LBR
RHOD GTPase cycle	1	203.9×	0.020	LBR
RHOG GTPase cycle	1	148.3×	0.020	LBR
RHOC GTPase cycle	1	146.4×	0.020	LBR
Metabolism of steroids	1	137.6×	0.020	LBR
RAC2 GTPase cycle	1	126.9×	0.020	LBR
RAC3 GTPase cycle	1	119.0×	0.020	LBR
Mitotic Metaphase and Anaphase	1	96.8×	0.021	LBR
Mitotic Anaphase	1	96.8×	0.021	LBR
RHOA GTPase cycle	1	74.6×	0.025	LBR
CDC42 GTPase cycle	1	72.3×	0.025	LBR
M Phase	1	66.0×	0.025	LBR
RAC1 GTPase cycle	1	61.1×	0.025	LBR
RHO GTPase cycle	1	60.1×	0.025	LBR
Cell Cycle, Mitotic	1	48.2×	0.030	LBR
Cell Cycle	1	36.0×	0.038	LBR
Signaling by Rho GTPases	1	34.2×	0.038	LBR
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.038	LBR
Metabolism of lipids	1	31.6×	0.038	LBR
RNA Polymerase II Transcription	1	22.5×	0.051	LBR
Gene expression (Transcription)	1	17.8×	0.063	LBR
Generic Transcription Pathway	1	15.1×	0.071	LBR
Metabolism	1	11.6×	0.089	LBR
Signal Transduction	1	10.2×	0.098	LBR

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
neutrophil differentiation	1	1872.4×	0.002	LBR
random inactivation of X chromosome	1	936.2×	0.002	LBR
cholesterol biosynthetic process	1	421.3×	0.002	LBR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LBR	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
LBR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LBR	1.3.1.70	DELTA14-sterol reductase

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

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)
LBR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.