X-linked chondrodysplasia punctata 1

Summary

X-linked chondrodysplasia punctata 1 (MONDO:0010555) is a disease caused by ARSL (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ARSL (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 64
• Phenotypes (HPO): 56

Clinical features

Signs & symptoms

Clinical features (HPO)

56 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000410	Mixed hearing impairment	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000925	Abnormality of the vertebral column	Frequent (30-79%)
HP:0001857	Short distal phalanx of toe	Frequent (30-79%)
HP:0002000	Short columella	Frequent (30-79%)
HP:0003508	Proportionate short stature	Frequent (30-79%)
HP:0008420	Punctate vertebral calcifications	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0010655	Epiphyseal stippling	Frequent (30-79%)
HP:0010666	Hypoplasia of the anterior nasal spine	Frequent (30-79%)
HP:0003316	Butterfly vertebrae	Occasional (5-29%)
HP:0003320	C1-C2 subluxation	Occasional (5-29%)
HP:0003416	Spinal canal stenosis	Occasional (5-29%)
HP:0003417	Coronal cleft vertebrae	Occasional (5-29%)
HP:0003467	Atlantoaxial instability	Occasional (5-29%)
HP:0004695	Calcaneal epiphyseal stippling	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0008417	Vertebral hypoplasia	Occasional (5-29%)
HP:0008434	Hypoplastic cervical vertebrae	Occasional (5-29%)
HP:0008445	Cervical spinal canal stenosis	Occasional (5-29%)
HP:0008469	Cervical vertebral dysplasia	Occasional (5-29%)
HP:0008754	Laryngeal calcification	Occasional (5-29%)
HP:0009107	Abnormal ossification involving the femoral head and neck	Occasional (5-29%)
HP:0009928	Thick nasal alae	Occasional (5-29%)
HP:0010171	Epiphyseal stippling of toe phalanges	Occasional (5-29%)
HP:0010255	Stippling of the epiphyses of the distal phalanges of the hand	Occasional (5-29%)
HP:0010646	Cervical spine instability	Occasional (5-29%)
HP:0025426	Abnormal bronchus morphology	Occasional (5-29%)
HP:3000052	Abnormality of hyoid bone	Occasional (5-29%)
HP:0002871	Central apnea	Occasional (5-29%)
HP:0002947	Cervical kyphosis	Occasional (5-29%)
HP:0000919	Abnormality of the costochondral junction	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001742	Nasal congestion	Occasional (5-29%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002341	Cervical cord compression	Occasional (5-29%)
HP:0002643	Neonatal respiratory distress	Occasional (5-29%)
HP:0002777	Tracheal stenosis	Occasional (5-29%)
HP:0002787	Tracheal calcification	Occasional (5-29%)
HP:0002789	Tachypnea	Occasional (5-29%)
HP:0010880	Increased nuchal translucency	Excluded (0%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000609	Optic nerve hypoplasia	Very rare (<1-4%)
HP:0001629	Ventricular septal defect	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked chondrodysplasia punctata 1
Mondo ID	MONDO:0010555
OMIM	302950
Orphanet	79345
UMLS	C3669395
MedGen	777171
GARD	0001296
Is cancer (heuristic)	no

Also known as: ARSE X-linked chondrodysplasia punctata · arse X-linked chondrodysplasia punctata · arylsulfatase E deficiency · brachytelephalangic chondrodysplasia punctata · CDPX1 · chondrodysplasia punctata 1 X-linked recessive · chondrodysplasia punctata 1, X-linked recessive · chondrodysplasia punctata brachytelephalangic · chondrodysplasia punctata, brachytelephalangic · chondrodysplasia punctata, X-linked recessive, X-linked recessive · CPXR · X-linked chondrodysplasia punctata 1 · X-linked chondrodysplasia punctata caused by mutation in ARSE · X-linked chondrodysplasia punctata caused by mutation in arse

Data availability: 64 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 1

Related subtypes (1): X-linked chondrodysplasia punctata 2

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

64 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 14 benign, 11 pathogenic, 9 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073287	NC_000023.10:g.(?2838632)(2878441_?)del	ARSD	Pathogenic	criteria provided, single submitter
11523	NM_000047.3(ARSL):c.349G>A (p.Gly117Arg)	ARSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11524	NM_000047.3(ARSL):c.332G>C (p.Arg111Pro)	ARSL	Pathogenic	no assertion criteria provided
11525	NM_000047.3(ARSL):c.410G>T (p.Gly137Val)	ARSL	Pathogenic	no assertion criteria provided
11526	NM_000047.3(ARSL):c.733G>C (p.Gly245Arg)	ARSL	Pathogenic	no assertion criteria provided
11527	NM_000047.3(ARSL):c.1475G>A (p.Cys492Tyr)	ARSL	Pathogenic	no assertion criteria provided
11528	NM_000047.3(ARSL):c.1732C>T (p.Pro578Ser)	ARSL	Pathogenic	no assertion criteria provided
1683481	NM_000047.3(ARSL):c.1289+1G>A	ARSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723873	NM_000047.3(ARSL):c.916A>G (p.Thr306Ala)	ARSL	Pathogenic	criteria provided, single submitter
3382548	NM_000047.3(ARSL):c.827del (p.Leu276fs)	ARSL	Pathogenic	criteria provided, single submitter
3382779	NM_000047.3(ARSL):c.294C>A (p.Tyr98Ter)	ARSL	Pathogenic	criteria provided, single submitter
657917	NC_000023.11:g.(?2934812)(2960420_?)del	ARSL	Pathogenic	criteria provided, single submitter
832204	NC_000023.11:g.(?2934812)(2958455_?)del	ARSL	Pathogenic	criteria provided, single submitter
1066074	NM_000047.3(ARSL):c.217G>A (p.Gly73Ser)	ARSL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698854	NM_000047.3(ARSL):c.1219G>T (p.Glu407Ter)	ARSL	Likely pathogenic	criteria provided, single submitter
1805736	NM_000047.3(ARSL):c.430G>A (p.Gly144Arg)	ARSL	Likely pathogenic	criteria provided, single submitter
21031	NM_000047.3(ARSL):c.119T>G (p.Ile40Ser)	ARSL	Likely pathogenic	criteria provided, single submitter
2690544	NM_000047.3(ARSL):c.991+2T>C	ARSL	Likely pathogenic	criteria provided, single submitter
3340124	NM_000047.3(ARSL):c.1108del (p.Trp370fs)	ARSL	Likely pathogenic	no assertion criteria provided
3382679	NM_000047.3(ARSL):c.694del (p.Leu232fs)	ARSL	Likely pathogenic	criteria provided, single submitter
4533272	NM_000047.3(ARSL):c.258C>A (p.Cys86Ter)	ARSL	Likely pathogenic	criteria provided, single submitter
11529	NM_000047.3(ARSL):c.1743G>A (p.Trp581Ter)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157732	NM_000047.3(ARSL):c.337C>T (p.Leu113Phe)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683192	NM_000047.3(ARSL):c.949G>A (p.Gly317Arg)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683210	NM_000047.3(ARSL):c.24-1G>A	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21033	NM_000047.3(ARSL):c.410G>C (p.Gly137Ala)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439211	NM_000047.3(ARSL):c.1265C>T (p.Ala422Val)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2737073	NM_000047.3(ARSL):c.1171G>A (p.Gly391Arg)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522724	NM_000047.3(ARSL):c.1189G>A (p.Gly397Arg)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547861	NM_000047.3(ARSL):c.1694T>G (p.Ile565Ser)	ARSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ARSL	Definitive	X-linked	X-linked chondrodysplasia punctata 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARSL	Orphanet:79345	Brachytelephalangic chondrodysplasia punctata

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
ARSL	HGNC:719	ENSG00000157399	P51690	Arylsulfatase L	gencc,clinvar
ARSD	HGNC:717	ENSG00000006756	P51689	Arylsulfatase D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARSL	Arylsulfatase L	Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate.

Protein-family classification

Druggable: 2 · 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
Phosphatase	2	83.9×	1e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARSL	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
ARSD	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

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
body of pancreas	1
liver	1
right lobe of liver	1
cardia of stomach	1
pylorus	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARSL	174	broad	marker	body of pancreas, liver, right lobe of liver
ARSD	263	ubiquitous	marker	renal medulla, cardia of stomach, pylorus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARSL	1,114
ARSD	956

Intra-cohort edges

A	B	Sources
ARSD	ARSL	biogrid_interaction, intact

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSD	P51689	92.71
ARSL	P51690	92.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
The activation of arylsulfatases	2	878.5×	1e-05	ARSL, ARSD
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	2	423.0×	2e-05	ARSL, ARSD
Glycosphingolipid metabolism	2	300.5×	3e-05	ARSL, ARSD
Glycosphingolipid catabolism	2	292.8×	3e-05	ARSL, ARSD
Sphingolipid metabolism	2	167.9×	6e-05	ARSL, ARSD
Metabolism of lipids	2	31.6×	0.002	ARSL, ARSD
Post-translational protein modification	2	19.2×	0.003	ARSL, ARSD
Metabolism of proteins	2	12.4×	0.007	ARSL, ARSD
Metabolism	2	11.6×	0.007	ARSL, ARSD

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
skeletal system development	1	125.8×	0.008	ARSL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
ARSL	0	0
ARSD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	ARSL, ARSD
E	Difficult family or no structure, no drug	0

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)
ARSL	0	—
ARSD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.