X-linked chondrodysplasia punctata 2

Summary

X-linked chondrodysplasia punctata 2 (MONDO:0020603) is a disease caused by EBP (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: EBP (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 71
• Phenotypes (HPO): 46

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.25	Europe	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0000951	Abnormality of the skin	Very frequent (80-99%)
HP:0010655	Epiphyseal stippling	Very frequent (80-99%)
HP:0000324	Facial asymmetry	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000929	Abnormal skull morphology	Frequent (30-79%)
HP:0001019	Erythroderma	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004468	Anomalous tracheal cartilage	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006619	Anterior rib punctate calcifications	Frequent (30-79%)
HP:0008064	Ichthyosis	Frequent (30-79%)
HP:0025474	Erythematous plaque	Frequent (30-79%)
HP:0040189	Scaling skin	Frequent (30-79%)
HP:0100559	Lower limb asymmetry	Frequent (30-79%)
HP:0100560	Upper limb asymmetry	Frequent (30-79%)
HP:0100569	Abnormally ossified vertebrae	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000653	Sparse eyelashes	Occasional (5-29%)
HP:0001197	Abnormality of prenatal development or birth	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002088	Abnormal lung morphology	Occasional (5-29%)
HP:0002208	Coarse hair	Occasional (5-29%)
HP:0002232	Patchy alopecia	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002999	Patellar dislocation	Occasional (5-29%)
HP:0004552	Scarring alopecia of scalp	Occasional (5-29%)
HP:0005756	Neonatal epiphyseal stippling	Occasional (5-29%)
HP:0008434	Hypoplastic cervical vertebrae	Occasional (5-29%)
HP:0008443	Spinal deformities	Occasional (5-29%)
HP:0008850	Severe postnatal growth retardation	Occasional (5-29%)
HP:0010720	Abnormal hair pattern	Occasional (5-29%)
HP:0045075	Sparse eyebrow	Occasional (5-29%)
HP:0000126	Hydronephrosis	Very rare (<1-4%)
HP:0000377	Abnormal pinna morphology	Very rare (<1-4%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0100702	Arachnoid cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked chondrodysplasia punctata 2
Mondo ID	MONDO:0020603
OMIM	302960
Orphanet	35173
DOID	DOID:0080352
UMLS	C0282102
MedGen	79381
GARD	0006189
NORD	1005
Is cancer (heuristic)	no

Also known as: CDPX2 · CDPXD · chondrodysplasia punctata 2 X-linked dominant · chondrodysplasia punctata 2, X-linked dominant · chondrodysplasia punctata caused by mutation in EBP · chondrodysplasia punctata, X-linked dominant, X-linked dominant · Conrad Hunermann Happle syndrome · Conradi Hunermann syndrome · Conradi Hünermann Syndrome · Conradi-Hunermann syndrome · Conradi-Hunermann-Happle syndrome · Conradi-Hünermann-Happle syndrome · EBP chondrodysplasia punctata · Happle syndrome · X-linked chondrodysplasia punctata type 2

Data availability: 71 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked chondrodysplasia punctata › X-linked chondrodysplasia punctata 2

Related subtypes (1): X-linked chondrodysplasia punctata 1

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

71 retrieved; paginated sample, class counts are floors:

28 pathogenic, 16 likely pathogenic, 13 uncertain significance, 7 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11483	NM_006579.3(EBP):c.87G>A (p.Trp29Ter)	EBP	Pathogenic	no assertion criteria provided
11484	NM_006579.3(EBP):c.187C>T (p.Arg63Ter)	EBP	Pathogenic	criteria provided, single submitter
11485	NM_006579.3(EBP):c.238G>A (p.Glu80Lys)	EBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11486	NM_006579.3(EBP):c.338+1G>T	EBP	Pathogenic	no assertion criteria provided
11487	NM_006579.3(EBP):c.390del (p.Pro131fs)	EBP	Pathogenic	no assertion criteria provided
11488	NM_006579.3(EBP):c.586_587insA (p.Trp196Ter)	EBP	Pathogenic	no assertion criteria provided
11489	NM_006579.3(EBP):c.386G>A (p.Trp129Ter)	EBP	Pathogenic	criteria provided, single submitter
11490	NM_006579.3(EBP):c.523C>T (p.Gln175Ter)	EBP	Pathogenic	no assertion criteria provided
11491	NM_006579.3(EBP):c.587G>A (p.Trp196Ter)	EBP	Pathogenic	no assertion criteria provided
11492	NM_006579.3(EBP):c.440G>A (p.Arg147His)	EBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1410474	NM_006579.3(EBP):c.184C>T (p.Arg62Trp)	EBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158530	NM_006579.3(EBP):c.141G>T (p.Trp47Cys)	EBP	Pathogenic	criteria provided, single submitter
158532	NM_006579.3(EBP):c.182G>A (p.Trp61Ter)	EBP	Pathogenic	criteria provided, single submitter
158533	NM_006579.3(EBP):c.204G>T (p.Trp68Cys)	EBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158536	NM_006579.3(EBP):c.292_296del (p.Ser98fs)	EBP	Pathogenic	criteria provided, single submitter
158538	NM_006579.3(EBP):c.301+2T>A	EBP	Pathogenic	criteria provided, single submitter
158540	NM_006579.3(EBP):c.304A>T (p.Lys102Ter)	EBP	Pathogenic	criteria provided, single submitter
158541	NM_006579.3(EBP):c.310T>C (p.Tyr104His)	EBP	Pathogenic	criteria provided, single submitter
158545	NM_006579.3(EBP):c.328C>T (p.Arg110Ter)	EBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158548	NM_006579.3(EBP):c.464_465del (p.Ser155fs)	EBP	Pathogenic	criteria provided, single submitter
158549	NM_006579.3(EBP):c.480T>G (p.Tyr160Ter)	EBP	Pathogenic	criteria provided, single submitter
1699251	NM_006579.3(EBP):c.338+1G>C	EBP	Pathogenic	criteria provided, single submitter
210902	NM_006579.3(EBP):c.225dup (p.His76fs)	EBP	Pathogenic	criteria provided, single submitter
210903	NM_006579.3(EBP):c.329_332dup (p.Tyr111Ter)	EBP	Pathogenic	criteria provided, single submitter
210905	NM_006579.3(EBP):c.423_427delinsT (p.Arg142fs)	EBP	Pathogenic	criteria provided, single submitter
210906	NM_006579.3(EBP):c.484dup (p.Asp162fs)	EBP	Pathogenic	criteria provided, single submitter
2501695	NM_006579.3(EBP):c.312T>A (p.Tyr104Ter)	EBP	Pathogenic	criteria provided, single submitter
4710748	NM_006579.3(EBP):c.558G>A (p.Trp186Ter)	EBP	Pathogenic	criteria provided, multiple submitters, no conflicts
803990	NM_006579.3(EBP):c.261C>G (p.Tyr87Ter)	EBP	Pathogenic	criteria provided, multiple submitters, no conflicts
803991	NM_006579.3(EBP):c.506_507del (p.Glu169fs)	EBP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 6 · 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
EBP	Definitive	X-linked	chondrodysplasia punctata 2, X-linked dominant	9
GLB1	Definitive	X-linked	chondrodysplasia punctata 2, X-linked dominant	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EBP	Orphanet:35173	X-linked dominant chondrodysplasia punctata
EBP	Orphanet:401973	MEND syndrome
GLB1	Orphanet:309310	Mucopolysaccharidosis type 4B
GLB1	Orphanet:79255	GM1 gangliosidosis type 1
GLB1	Orphanet:79256	GM1 gangliosidosis type 2
GLB1	Orphanet:79257	GM1 gangliosidosis type 3

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
EBP	HGNC:3133	ENSG00000147155	Q15125	3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase	gencc,clinvar
GLB1	HGNC:4298	ENSG00000170266	P16278	Beta-galactosidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EBP	3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase	Isomerase that catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers a catalytic step in the postlanosterol biosynthesis of cholesterol.
GLB1	Beta-galactosidase	Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.

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)
EBP	Enzyme (other)	yes	5.3.3.5	EBP, EXPERA
GLB1	Other/Unknown	no		Glycoside_Hdrlase_35, Galactose-bd-like_sf, GH_hydrolase_sf

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
right adrenal gland	1
right adrenal gland cortex	1
right lobe of liver	1
monocyte	1
mononuclear cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EBP	288	ubiquitous	marker	right lobe of liver, right adrenal gland, right adrenal gland cortex
GLB1	258	ubiquitous	marker	monocyte, mononuclear cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EBP	1,684
GLB1	1,578

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLB1	P16278	8
EBP	Q15125	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS IV - Morquio syndrome B (Keratin metabolism)	1	2855.0×	0.006	GLB1
MPS IV - Morquio syndrome B (CS/DS degradation)	1	2855.0×	0.006	GLB1
Defective NEU1 causes sialidosis	1	1427.5×	0.006	GLB1
Cholesterol biosynthesis from zymosterol (modified Kandutsch-Russell pathway)	1	1427.5×	0.006	EBP
Mucopolysaccharidoses	1	951.7×	0.007	GLB1
Cholesterol biosynthesis via desmosterol (Bloch pathway)	1	571.0×	0.009	EBP
Diseases of carbohydrate metabolism	1	407.9×	0.010	GLB1
Keratan sulfate degradation	1	356.9×	0.010	GLB1
Diseases associated with N-glycosylation of proteins	1	317.2×	0.010	GLB1
Heparan sulfate/heparin (HS-GAG) metabolism	1	271.9×	0.010	GLB1
CS/DS degradation	1	271.9×	0.010	GLB1
Keratan sulfate/keratin metabolism	1	248.3×	0.010	GLB1
HS-GAG degradation	1	248.3×	0.010	GLB1
Sialic acid metabolism	1	163.1×	0.013	GLB1
Glycosphingolipid metabolism	1	150.3×	0.013	GLB1
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.013	GLB1
Glycosphingolipid catabolism	1	146.4×	0.013	GLB1
Glycosaminoglycan metabolism	1	109.8×	0.016	GLB1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.016	GLB1
Sphingolipid metabolism	1	84.0×	0.019	GLB1
Diseases of glycosylation	1	65.6×	0.023	GLB1
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.024	GLB1
Diseases of metabolism	1	40.2×	0.034	GLB1
Asparagine N-linked glycosylation	1	30.1×	0.044	GLB1
Metabolism of lipids	1	15.8×	0.080	GLB1
Innate Immune System	1	12.8×	0.095	GLB1
Neutrophil degranulation	1	11.5×	0.101	GLB1
Post-translational protein modification	1	9.6×	0.116	GLB1
Disease	1	6.5×	0.158	GLB1
Immune System	1	6.5×	0.158	GLB1

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
response to cortisone	1	4213.0×	0.002	GLB1
keratan sulfate proteoglycan catabolic process	1	2808.7×	0.002	GLB1
response to Thyroglobulin triiodothyronine	1	2808.7×	0.002	GLB1
obsolete cholesterol biosynthetic process via desmosterol	1	2106.5×	0.002	EBP
galactose catabolic process	1	1404.3×	0.002	GLB1
obsolete cholesterol biosynthetic process via lathosterol	1	1053.2×	0.002	EBP
ganglioside catabolic process	1	936.2×	0.002	GLB1
ossification involved in bone maturation	1	702.2×	0.002	EBP
glycoprotein catabolic process	1	526.6×	0.003	GLB1
cholesterol biosynthetic process	1	210.7×	0.006	EBP
hemopoiesis	1	133.8×	0.009	EBP
cholesterol metabolic process	1	98.0×	0.011	EBP
carbohydrate metabolic process	1	68.0×	0.015	GLB1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
EBP	TRIFLUPERIDOL
GLB1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EBP	16	4
GLB1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIFLUPERIDOL	4	EBP
TRIPARANOL	4	EBP
BUFLOMEDIL	4	EBP
TRIFLUOPERAZINE	4	EBP
HALOPERIDOL	4	EBP
NAFTIFINE	4	EBP
AMIODARONE	4	EBP
RALOXIFENE	4	EBP
TAMOXIFEN	4	EBP
DOXORUBICIN	4	EBP
MIGALASTAT	4	GLB1
OPIPRAMOL	3	EBP
ENCLOMIPHENE	3	EBP
ZUCLOMIPHENE	2	EBP
LEVEMOPAMIL	2	EBP
NAFOXIDINE	2	EBP
RONIPAMIL	2	EBP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GLB1	124	Binding:123, ADMET:1
EBP	57	Binding:34, Functional:23

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EBP	5.3.3.5	cholestenol DELTA-isomerase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLB1	124

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

17 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.

Compound	Max phase	Cohort target (bioactivity)
TRIFLUPERIDOL	4	EBP
TRIPARANOL	4	EBP
BUFLOMEDIL	4	EBP
TRIFLUOPERAZINE	4	EBP
HALOPERIDOL	4	EBP
NAFTIFINE	4	EBP
AMIODARONE	4	EBP
RALOXIFENE	4	EBP
TAMOXIFEN	4	EBP
DOXORUBICIN	4	EBP
MIGALASTAT	4	GLB1
OPIPRAMOL	3	EBP
ENCLOMIPHENE	3	EBP
ZUCLOMIPHENE	2	EBP
LEVEMOPAMIL	2	EBP
NAFOXIDINE	2	EBP
RONIPAMIL	2	EBP

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	EBP, GLB1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.