Greenberg dysplasia

Summary

Greenberg dysplasia (MONDO:0008974) is a disease caused by LBR (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LBR (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 106
• Phenotypes (HPO): 18

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

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001004	Lymphedema	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001881	Abnormal leukocyte morphology	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0006619	Anterior rib punctate calcifications	Very frequent (80-99%)
HP:0008890	Severe short-limb dwarfism	Very frequent (80-99%)
HP:0008905	Rhizomelia	Very frequent (80-99%)
HP:0009106	Abnormal pelvis bone ossification	Very frequent (80-99%)
HP:0011849	Abnormal bone ossification	Very frequent (80-99%)
HP:0100569	Abnormally ossified vertebrae	Very frequent (80-99%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000774	Narrow chest	Frequent (30-79%)
HP:0001362	Skull defect	Frequent (30-79%)
HP:0004331	Decreased skull ossification	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0100602	Preeclampsia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Greenberg dysplasia
Mondo ID	MONDO:0008974
MeSH	C535858
OMIM	215140
Orphanet	1426
DOID	DOID:0111588
ICD-11	1858458540
SNOMED CT	389261002
UMLS	C2931048
MedGen	418969
GARD	0008754
Is cancer (heuristic)	no

Also known as: autosomal recessive lethal chondrodystrophy with congenital hydrops · GRBGD · Greenberg dysplasia · Greenberg skeletal dysplasia · hem · hem dysplasia · hem/Greenberg dysplasia · hydrops, ectopic calcification, moth-eaten skeletal dysplasia · hydrops-ectopic calcification-motheaten syndrome · skeletal dysplasia, Greenberg type

Data availability: 106 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › sterol biosynthesis disorder › Greenberg dysplasia

Related subtypes (6): MEND syndrome, X-linked chondrodysplasia punctata, CHILD syndrome, microcephaly-congenital cataract-psoriasiform dermatitis syndrome, mevalonate kinase deficiency, cholesterol biosynthetic process disease

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

106 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 25 conflicting classifications of pathogenicity, 9 benign, 7 pathogenic, 5 benign/likely benign, 4 pathogenic/likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100900	NM_002296.4(LBR):c.1639A>G (p.Asn547Asp)	LBR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100901	NM_002296.4(LBR):c.1748G>A (p.Arg583Gln)	LBR	Pathogenic	criteria provided, single submitter
100902	NM_002296.4(LBR):c.32_35del (p.Val11fs)	LBR	Pathogenic	no assertion criteria provided
100903	NM_002296.4(LBR):c.1402del (p.Tyr468fs)	LBR	Pathogenic	no assertion criteria provided
1339424	NM_002296.4(LBR):c.366+1G>T	LBR	Pathogenic	no assertion criteria provided
1339425	NM_002296.4(LBR):c.1379A>G (p.Asp460Gly)	LBR	Pathogenic	no assertion criteria provided
224875	NM_002296.4(LBR):c.1640A>G (p.Asn547Ser)	LBR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224876	NM_002296.4(LBR):c.226C>T (p.Arg76Ter)	LBR	Pathogenic	criteria provided, single submitter
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
9529	NM_002296.4(LBR):c.1599_1605delinsCTAGAAG (p.Leu534_Leu535delinsTer)	LBR	Pathogenic	no assertion criteria provided
218605	NM_002296.4(LBR):c.866G>A (p.Gly289Glu)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235704	NM_002296.4(LBR):c.1609T>G (p.Ser537Ala)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295934	NM_002296.4(LBR):c.1324T>C (p.Leu442=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295935	NM_002296.4(LBR):c.1188+4T>C	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295938	NM_002296.4(LBR):c.951A>G (p.Val317=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295939	NM_002296.4(LBR):c.899A>G (p.Tyr300Cys)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295942	NM_002296.4(LBR):c.790C>T (p.Leu264=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295943	NM_002296.4(LBR):c.746C>A (p.Ala249Asp)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295946	NM_002296.4(LBR):c.396T>C (p.Tyr132=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295948	NM_002296.4(LBR):c.97A>G (p.Thr33Ala)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295950	NM_002296.4(LBR):c.21C>T (p.Ala7=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
295952	NM_002296.4(LBR):c.-39G>C	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426800	NM_002296.4(LBR):c.1366C>G (p.Leu456Val)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710682	NM_002296.4(LBR):c.819C>T (p.Tyr273=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715943	NM_002296.4(LBR):c.931A>G (p.Thr311Ala)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725544	NM_002296.4(LBR):c.312C>T (p.Ala104=)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730151	NM_002296.4(LBR):c.1289A>G (p.Tyr430Cys)	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732559	NM_002296.4(LBR):c.1315-10A>G	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
736744	NM_002296.4(LBR):c.1315-8C>T	LBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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.