Silverman-Handmaker type dyssegmental dysplasia

Summary

Silverman-Handmaker type dyssegmental dysplasia (MONDO:0009140) is a disease caused by HSPG2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HSPG2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 553
• Phenotypes (HPO): 41

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000470	Short neck	Frequent (30-79%)
HP:0000774	Narrow chest	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002879	Anisospondyly	Frequent (30-79%)
HP:0002979	Bowing of the legs	Frequent (30-79%)
HP:0002983	Micromelia	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003510	Severe short stature	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0012368	Flat face	Frequent (30-79%)
HP:0040064	Abnormality of limbs	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000119	Abnormality of the genitourinary system	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000773	Short ribs	Occasional (5-29%)
HP:0000946	Hypoplastic ilia	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001059	Pterygium	Occasional (5-29%)
HP:0001195	Single umbilical artery	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0002084	Encephalocele	Occasional (5-29%)
HP:0002089	Pulmonary hypoplasia	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0003173	Hypoplastic pubic bone	Occasional (5-29%)
HP:0003175	Hypoplastic ischia	Occasional (5-29%)
HP:0005622	Broad long bones	Occasional (5-29%)
HP:0032548	Increased placental thickness	Occasional (5-29%)
HP:0100759	Clubbing of fingers	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Silverman-Handmaker type dyssegmental dysplasia
Mondo ID	MONDO:0009140
MeSH	C537998
OMIM	224410
Orphanet	1865
DOID	DOID:0090032
SNOMED CT	93132001
UMLS	C1857100
MedGen	347372
GARD	0002026
Is cancer (heuristic)	no

Also known as: Anisospondylic camptomicromelic dwarfism Silverman-Handmaker type · DDSH · dyssegmental dwarfism Silverman-Handmaker type · dyssegmental dysplasia Silverman-Handmaker type · dyssegmental dysplasia, Silverman-Handmaker type

Data availability: 553 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of perlecan › Silverman-Handmaker type dyssegmental dysplasia

Related subtypes (1): Schwartz-Jampel syndrome

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

553 retrieved; paginated sample, class counts are floors:

242 uncertain significance, 146 conflicting classifications of pathogenicity, 76 benign, 61 benign/likely benign, 12 likely pathogenic, 7 pathogenic, 6 likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034182	NM_005529.7(HSPG2):c.12900-2A>C	HSPG2	Pathogenic	criteria provided, single submitter
1177407	NM_005529.7(HSPG2):c.3518del (p.Gly1173fs)	HSPG2	Pathogenic	criteria provided, single submitter
1323078	NM_005529.7(HSPG2):c.9033_9034del (p.Pro3011_Ser3012insTer)	HSPG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14919	HSPG2, 89-BP DUP, EX34	HSPG2	Pathogenic	no assertion criteria provided
14920	NM_005529.7(HSPG2):c.6724+5G>A	HSPG2	Pathogenic	no assertion criteria provided
14921	HSPG2, 10328C-T	HSPG2	Pathogenic	no assertion criteria provided
265454	NM_005529.7(HSPG2):c.7006+1G>A	HSPG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
284213	NM_005529.7(HSPG2):c.10894C>T (p.Arg3632Ter)	HSPG2	Pathogenic	criteria provided, multiple submitters, no conflicts
3255569	NM_005529.7(HSPG2):c.7294+1G>C	HSPG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819065	NM_005529.7(HSPG2):c.3268C>T (p.Arg1090Ter)	HSPG2	Pathogenic	criteria provided, single submitter
1064625	NM_005529.7(HSPG2):c.4955+3A>T	HSPG2	Likely pathogenic	criteria provided, single submitter
1685350	NM_005529.7(HSPG2):c.9514-1G>A	HSPG2	Likely pathogenic	criteria provided, single submitter
2431557	NM_005529.7(HSPG2):c.6259C>T (p.Arg2087Ter)	HSPG2	Likely pathogenic	criteria provided, single submitter
3236425	NM_005529.7(HSPG2):c.11562+1G>A	HSPG2	Likely pathogenic	criteria provided, single submitter
3381885	NM_005529.7(HSPG2):c.8025+1G>A	HSPG2	Likely pathogenic	criteria provided, single submitter
3600345	NM_005529.7(HSPG2):c.5112del (p.His1706fs)	HSPG2	Likely pathogenic	criteria provided, single submitter
3896882	NM_005529.7(HSPG2):c.6288+1G>A	HSPG2	Likely pathogenic	criteria provided, single submitter
4081448	NM_005529.7(HSPG2):c.5015-1G>A	HSPG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819064	NM_005529.7(HSPG2):c.3656+1G>A	HSPG2	Likely pathogenic	criteria provided, single submitter
800919	NM_005529.7(HSPG2):c.11671+1G>T	HSPG2	Likely pathogenic	no assertion criteria provided
930864	NM_005529.7(HSPG2):c.6437del (p.Pro2146fs)	HSPG2	Likely pathogenic	criteria provided, single submitter
982057	NM_005529.7(HSPG2):c.9970G>A (p.Gly3324Arg)	HSPG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1031544	NM_005529.7(HSPG2):c.8025+20C>T	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051273	NM_005529.7(HSPG2):c.11751G>A (p.Ser3917=)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400608	NM_005529.7(HSPG2):c.6161A>G (p.Lys2054Arg)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194641	NM_005529.7(HSPG2):c.2074G>A (p.Val692Met)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197080	NM_005529.7(HSPG2):c.4916C>T (p.Thr1639Met)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197081	NM_005529.7(HSPG2):c.4928C>A (p.Pro1643His)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198007	NM_005529.7(HSPG2):c.7438C>T (p.Arg2480Trp)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198958	NM_005529.7(HSPG2):c.11475C>T (p.Ile3825=)	HSPG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
HSPG2	Definitive	Autosomal recessive	Silverman-Handmaker type dyssegmental dysplasia	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSPG2	Orphanet:1606	1p36 deletion syndrome
HSPG2	Orphanet:1865	Dyssegmental dysplasia, Silverman-Handmaker type
HSPG2	Orphanet:800	Schwartz-Jampel syndrome

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
HSPG2	HGNC:5273	ENSG00000142798	P98160	Basement membrane-specific heparan sulfate proteoglycan core protein	gencc,clinvar
LDLRAD2	HGNC:32071	ENSG00000187942	Q5SZI1	Low-density lipoprotein receptor class A domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSPG2	Basement membrane-specific heparan sulfate proteoglycan core protein	Integral component of basement membranes.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSPG2	Antibody/Immunoglobulin	yes		Laminin_IV, SEA_dom, EGF
LDLRAD2	Other/Unknown	no		LDrepeatLR_classA_rpt, Sperma_CUB_dom_sf, LDL_receptor-like_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
popliteal artery	2
tibial artery	2
saphenous vein	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSPG2	271	ubiquitous	marker	saphenous vein, popliteal artery, tibial artery
LDLRAD2	132		marker	sural nerve, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPG2	2,463
LDLRAD2	196

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSPG2	P98160	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LDLRAD2	Q5SZI1	79.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 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 EXT2 causes exostoses 2	1	815.7×	0.005	HSPG2
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	815.7×	0.005	HSPG2
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.005	HSPG2
Attachment and Entry	1	601.0×	0.005	HSPG2
Defective B4GALT7 causes EDS, progeroid type	1	571.0×	0.005	HSPG2
Defective B3GAT3 causes JDSSDHD	1	571.0×	0.005	HSPG2
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	571.0×	0.005	HSPG2
HS-GAG degradation	1	496.5×	0.005	HSPG2
Respiratory syncytial virus (RSV) attachment and entry	1	496.5×	0.005	HSPG2
Initiation of coagulation cascade	1	475.8×	0.005	HSPG2
Glycosaminoglycan-protein linkage region biosynthesis	1	393.8×	0.005	HSPG2
Laminin interactions	1	380.7×	0.005	HSPG2
HS-GAG biosynthesis	1	346.1×	0.005	HSPG2
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.006	HSPG2
Dengue Virus Attachment and Entry	1	259.6×	0.006	HSPG2
Retinoid metabolism and transport	1	248.3×	0.006	HSPG2
Regulation of clotting cascade	1	233.1×	0.006	HSPG2
RSV-host interactions	1	156.4×	0.008	HSPG2
Non-integrin membrane-ECM interactions	1	154.3×	0.008	HSPG2
ECM proteoglycans	1	150.3×	0.008	HSPG2
Integrin cell surface interactions	1	134.3×	0.009	HSPG2
Degradation of the extracellular matrix	1	117.7×	0.009	HSPG2
Amyloid fiber formation	1	102.9×	0.010	HSPG2
Dengue Virus-Host Interactions	1	45.7×	0.022	HSPG2

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
negative regulation of synaptic transmission, cholinergic	1	5617.3×	0.003	HSPG2
circulatory system development	1	1404.3×	0.006	HSPG2
protein localization to synapse	1	766.0×	0.007	HSPG2
animal organ regeneration	1	601.9×	0.007	HSPG2
negative regulation of cell adhesion	1	383.0×	0.009	HSPG2
embryo implantation	1	351.1×	0.009	HSPG2
positive regulation of endothelial cell proliferation	1	230.8×	0.010	HSPG2
receptor-mediated endocytosis	1	221.7×	0.010	HSPG2
smoothened signaling pathway	1	181.2×	0.011	HSPG2
negative regulation of angiogenesis	1	168.5×	0.011	HSPG2
response to hypoxia	1	95.8×	0.016	HSPG2
lipid metabolic process	1	91.6×	0.016	HSPG2
brain development	1	79.5×	0.017	HSPG2
response to xenobiotic stimulus	1	69.1×	0.019	HSPG2
angiogenesis	1	62.4×	0.019	HSPG2
negative regulation of cell population proliferation	1	42.1×	0.027	HSPG2
inflammatory response	1	37.7×	0.028	HSPG2
cell differentiation	1	29.1×	0.034	HSPG2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSPG2	0	0
LDLRAD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HSPG2	2	Binding:2

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	1	HSPG2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LDLRAD2

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)
HSPG2	2	—
LDLRAD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.