Diastrophic dysplasia

Summary

Diastrophic dysplasia (MONDO:0009107) is a disease caused by SLC26A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: SLC26A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 762
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.2	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.3	Europe	Validated
Point prevalence	1-9 / 100 000	3.03	Finland	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000889	Abnormality of the clavicle	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0008434	Hypoplastic cervical vertebrae	Very frequent (80-99%)
HP:0008921	Neonatal short-limb short stature	Very frequent (80-99%)
HP:0009381	Short finger	Very frequent (80-99%)
HP:0009623	Proximal placement of thumb	Very frequent (80-99%)
HP:0009748	Large earlobe	Very frequent (80-99%)
HP:0009773	Symphalangism affecting the phalanges of the hand	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000396	Overfolded helix	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0001234	Hitchhiker thumb	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001373	Joint dislocation	Frequent (30-79%)
HP:0001385	Hip dysplasia	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0001852	Sandal gap	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0002947	Cervical kyphosis	Frequent (30-79%)
HP:0005619	Thoracolumbar kyphosis	Frequent (30-79%)
HP:0005857	Cervical spina bifida	Frequent (30-79%)
HP:0009465	Ulnar deviation of finger	Frequent (30-79%)
HP:0034392	Joint contracture	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	diastrophic dysplasia
Mondo ID	MONDO:0009107
MeSH	C536170
OMIM	222600
Orphanet	628
DOID	DOID:14687
ICD-10-CM	Q77.5
ICD-11	1681550532
NCIT	C156311
SNOMED CT	58561002
UMLS	C0220726
MedGen	113103
GARD	0006275
NORD	1051
Is cancer (heuristic)	no

Also known as: DD · diastrophic dysplasia · DTD

Data availability: 762 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › diastrophic dysplasia

Related subtypes (12): iron metabolism disease, phosphorus metabolism disease, potassium deficiency disease, calcium metabolic disease, spondyloepiphyseal dysplasia with congenital joint dislocations, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, achondrogenesis type IB, chondrodysplasia with joint dislocations, gPAPP type, spondyloepimetaphyseal dysplasia, PAPSS2 type, acquired mineral metabolism disease, sulfur metabolism 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

600 retrieved; paginated sample, class counts are floors:

250 likely benign, 174 uncertain significance, 56 pathogenic, 37 conflicting classifications of pathogenicity, 35 pathogenic/likely pathogenic, 25 likely pathogenic, 12 benign/likely benign, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067905	NM_000112.4(SLC26A2):c.2065_2066del (p.Thr689fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1070109	NM_000112.4(SLC26A2):c.1714del (p.Leu572fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070678	NM_000112.4(SLC26A2):c.1441dup (p.Ser481fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071456	NM_000112.4(SLC26A2):c.1246C>T (p.Gln416Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285445	NM_000112.4(SLC26A2):c.1994dup (p.His665fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326262	NM_000112.4(SLC26A2):c.796dup (p.Thr266fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1374813	NM_000112.4(SLC26A2):c.1203_1204insTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACGGGGTTTCACCTTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCATTTTCT (p.Glu402delinsPhePhePhePhePhePheXaaXaaXaaXaaThrGlyPheHisLeuValSerGlnAspGlyLeuAspLeuLeuThrSerTer)	SLC26A2	Pathogenic	criteria provided, single submitter
1378416	NM_000112.4(SLC26A2):c.1397dup (p.Leu466fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388388	NM_000112.4(SLC26A2):c.1810_1811del (p.Val604fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1402115	NM_000112.4(SLC26A2):c.1393_1394del (p.Leu465fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1412823	NM_000112.4(SLC26A2):c.1592del (p.Leu531fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1419742	NM_000112.4(SLC26A2):c.2004_2007del (p.Glu669fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1436633	NM_000112.4(SLC26A2):c.1155del (p.Asp385fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1452842	NM_000112.4(SLC26A2):c.1147_1150del (p.Val382_Ala383insTer)	SLC26A2	Pathogenic	criteria provided, single submitter
1452846	NM_000112.4(SLC26A2):c.1772del (p.Asn591fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1453452	NM_000112.4(SLC26A2):c.100del (p.Glu34fs)	SLC26A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1453498	NM_000112.4(SLC26A2):c.58_62dup (p.Asp21fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1453606	NM_000112.4(SLC26A2):c.218del (p.Lys73fs)	SLC26A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1453912	NM_000112.4(SLC26A2):c.1720del (p.Ile574fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1454165	NM_000112.4(SLC26A2):c.78_88dup (p.Glu30fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1456395	NM_000112.4(SLC26A2):c.1272dup (p.Asn425Ter)	SLC26A2	Pathogenic	criteria provided, single submitter
1456546	NM_000112.4(SLC26A2):c.1306del (p.Thr436fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1456961	NM_000112.4(SLC26A2):c.1064_1065insAAAAA (p.Asn355fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1458581	NM_000112.4(SLC26A2):c.1639C>T (p.Gln547Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683433	NM_000112.4(SLC26A2):c.1773_1776del (p.Asn591fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683434	NM_000112.4(SLC26A2):c.1114A>T (p.Lys372Ter)	SLC26A2	Pathogenic	criteria provided, single submitter
1683435	NM_000112.4(SLC26A2):c.306C>G (p.Tyr102Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702483	NM_000112.4(SLC26A2):c.1487_1488insGGCG (p.Lys497fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878283	NM_000112.4(SLC26A2):c.1448T>C (p.Leu483Pro)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189077	NM_000112.4(SLC26A2):c.451del (p.Tyr151fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
SLC26A2	Definitive	Autosomal recessive	SLC26A2-related skeletal dysplasia	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC26A2	Orphanet:56304	Atelosteogenesis type II
SLC26A2	Orphanet:628	Diastrophic dysplasia
SLC26A2	Orphanet:93298	Achondrogenesis type 1B
SLC26A2	Orphanet:93307	Multiple epiphyseal dysplasia type 4

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
SLC26A2	HGNC:10994	ENSG00000155850	P50443	Sulfate transporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC26A2	Sulfate transporter	Sulfate transporter which mediates sulfate uptake into chondrocytes in order to maintain adequate sulfation of proteoglycans which is needed for cartilage development.

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC26A2	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

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
colonic mucosa	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC26A2	282	ubiquitous	marker	colonic mucosa, mucosa of sigmoid colon, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC26A2	1,793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC26A2	P50443	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Defective SLC26A2 causes chondrodysplasias	1	11420.0×	0.002	SLC26A2
Transport and metabolism of PAPS	1	1631.4×	0.005	SLC26A2
Inorganic anion exchange by SLC26 transporters	1	1268.9×	0.005	SLC26A2
Diseases associated with glycosaminoglycan metabolism	1	761.3×	0.006	SLC26A2
Cytosolic sulfonation of small molecules	1	519.1×	0.007	SLC26A2
Phase II - Conjugation of compounds	1	278.5×	0.011	SLC26A2
Glycosaminoglycan metabolism	1	219.6×	0.011	SLC26A2
SLC transporter disorders	1	203.9×	0.011	SLC26A2
Disorders of transmembrane transporters	1	139.3×	0.012	SLC26A2
Diseases of glycosylation	1	131.3×	0.012	SLC26A2
Biological oxidations	1	129.8×	0.012	SLC26A2
R-HSA-425393	1	129.8×	0.012	SLC26A2
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	SLC26A2
Diseases of metabolism	1	80.4×	0.016	SLC26A2
SLC-mediated transmembrane transport	1	59.2×	0.020	SLC26A2
Transport of small molecules	1	25.1×	0.045	SLC26A2
Disease	1	13.1×	0.081	SLC26A2
Metabolism	1	11.6×	0.086	SLC26A2

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
oxalate transport	1	2407.4×	0.002	SLC26A2
sulfate transmembrane transport	1	1203.7×	0.002	SLC26A2
chondrocyte proliferation	1	1053.2×	0.002	SLC26A2
chondrocyte differentiation	1	300.9×	0.004	SLC26A2
chloride transmembrane transport	1	237.3×	0.004	SLC26A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SLC26A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SLC26A2
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)
SLC26A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.