Geroderma osteodysplastica

Summary

Geroderma osteodysplastica (MONDO:0009271) is a disease caused by GORAB (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GORAB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 96
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002953	Vertebral compression fracture	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0004568	Beaking of vertebral bodies	Very frequent (80-99%)
HP:0004586	Biconcave vertebral bodies	Very frequent (80-99%)
HP:0011849	Abnormal bone ossification	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002827	Hip dislocation	Frequent (30-79%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000504	Abnormality of vision	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0007495	Prematurely aged appearance	Occasional (5-29%)
HP:0100790	Hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	geroderma osteodysplastica
Mondo ID	MONDO:0009271
MeSH	C537799
OMIM	231070
Orphanet	2078
DOID	DOID:0111266
SNOMED CT	254116003
UMLS	C0432255
MedGen	98149
GARD	0000413
Is cancer (heuristic)	no

Also known as: geroderma osteodysplastica · GERODERMA OSTEODYSPLASTICUM · Geroderma osteodysplasticum · GO

Data availability: 96 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited cutis laxa › geroderma osteodysplastica

Related subtypes (13): craniofaciofrontodigital syndrome, arterial tortuosity syndrome, ALDH18A1-related de Barsy syndrome, autosomal recessive cutis laxa type 2, classic type, occipital horn syndrome, RIN2 syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, PYCR1-related de Barsy syndrome, autosomal dominant cutis laxa, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, cutis laxa, autosomal recessive, type 2E, arterial tortuosity-bone fragility 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

96 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 14 benign, 8 pathogenic, 6 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 likely pathogenic, 3 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703424	NM_152281.3(GORAB):c.103C>T (p.Arg35Ter)	GORAB	Pathogenic	criteria provided, multiple submitters, no conflicts
218115	NM_152281.3(GORAB):c.658G>C (p.Ala220Pro)	GORAB	Pathogenic	criteria provided, single submitter
225381	NM_152281.3(GORAB):c.408_409del (p.Lys137fs)	GORAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2436670	NM_152281.3(GORAB):c.190C>T (p.Gln64Ter)	GORAB	Pathogenic	criteria provided, multiple submitters, no conflicts
2650	NM_152281.3(GORAB):c.367G>T (p.Glu123Ter)	GORAB	Pathogenic	criteria provided, single submitter
2652	NM_152281.3(GORAB):c.784C>T (p.Arg262Ter)	GORAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2653	NM_152281.3(GORAB):c.662+5G>C	GORAB	Pathogenic	no assertion criteria provided
2654	GORAB, 1-BP DEL, 257C	GORAB	Pathogenic	no assertion criteria provided
2734028	NM_152281.3(GORAB):c.257del (p.Pro86fs)	GORAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3391817	NM_152281.3(GORAB):c.316C>T (p.Gln106Ter)	GORAB	Pathogenic	criteria provided, single submitter
623306	NM_152281.2(GORAB):c.-1_1delGAinsCT (p.Met(?_1)_Met1(?))	GORAB	Pathogenic/Likely pathogenic	no assertion criteria provided
632088	NM_152281.3(GORAB):c.118C>T (p.Arg40Ter)	GORAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800784	NM_152281.3(GORAB):c.231dup (p.Pro78fs)	GORAB	Pathogenic	criteria provided, single submitter
1802239	NM_152281.3(GORAB):c.287del (p.Gly96fs)	GORAB	Likely pathogenic	criteria provided, single submitter
3573929	NM_152281.3(GORAB):c.521+2T>G	GORAB	Likely pathogenic	criteria provided, single submitter
3731408	NM_152281.3(GORAB):c.1A>G (p.Met1Val)	GORAB	Likely pathogenic	criteria provided, single submitter
804379	NM_152281.3(GORAB):c.5del (p.Ala2fs)	GORAB	Likely pathogenic	criteria provided, single submitter
293653	NM_152281.3(GORAB):c.276C>T (p.Thr92=)	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293654	NM_152281.3(GORAB):c.282C>G (p.Pro94=)	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293656	NM_152281.3(GORAB):c.522-9A>T	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875795	NM_152281.3(GORAB):c.1064G>T (p.Cys355Phe)	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876745	NM_152281.3(GORAB):c.-57T>C	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876747	NM_152281.3(GORAB):c.61+13G>T	GORAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013262	NM_152281.3(GORAB):c.-21G>A	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1013263	NM_152281.3(GORAB):c.648C>G (p.Asp216Glu)	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032478	NM_152281.3(GORAB):c.785G>A (p.Arg262Gln)	GORAB	Uncertain significance	criteria provided, single submitter
1059550	NM_152281.3(GORAB):c.408G>C (p.Lys136Asn)	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1391742	NM_152281.3(GORAB):c.868G>A (p.Glu290Lys)	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1416394	NM_152281.3(GORAB):c.658G>A (p.Ala220Thr)	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1446136	NM_152281.3(GORAB):c.388G>A (p.Asp130Asn)	GORAB	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · 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
GORAB	Definitive	Autosomal recessive	geroderma osteodysplastica	6
PYCR1	Supportive	Autosomal recessive	geroderma osteodysplastica	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GORAB	Orphanet:2078	Geroderma osteodysplastica
PYCR1	Orphanet:2078	Geroderma osteodysplastica
PYCR1	Orphanet:293633	PYCR1-related De Barsy syndrome
PYCR1	Orphanet:357064	Autosomal recessive cutis laxa type 2B

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GORAB	HGNC:25676	ENSG00000120370	Q5T7V8	RAB6-interacting golgin	gencc,clinvar
PYCR1	HGNC:9721	ENSG00000183010	P32322	Pyrroline-5-carboxylate reductase 1, mitochondrial	gencc
GORAB-AS1	HGNC:54051	ENSG00000231407		GORAB antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYCR1	Pyrroline-5-carboxylate reductase 1, mitochondrial	Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GORAB	Other/Unknown	no		GORAB
PYCR1	Enzyme (other)	yes	1.5.1.2	Pyrroline-COOH_reductase, 6-PGluconate_DH-like_C_sf, P5C_Rdtase_cat_N
GORAB-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
endothelial cell	1
rectum	1
body of pancreas	1
parotid gland	1
stromal cell of endometrium	1
colonic epithelium	1
cortical plate	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GORAB	244	ubiquitous	yes	calcaneal tendon, rectum, endothelial cell
PYCR1	224	ubiquitous	marker	stromal cell of endometrium, body of pancreas, parotid gland
GORAB-AS1	130		yes	colonic epithelium, primordial germ cell in gonad, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PYCR1	2,239
GORAB	877
GORAB-AS1	0

Intra-cohort edges

A	B	Sources
GORAB	PYCR1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PYCR1	P32322	47

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GORAB	Q5T7V8	71.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Glutamate and glutamine metabolism	1	815.7×	0.001	PYCR1

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
L-proline biosynthetic process	1	1404.3×	0.006	PYCR1
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	648.1×	0.006	PYCR1
dorsal/ventral neural tube patterning	1	401.2×	0.006	GORAB
regulation of mitochondrial membrane potential	1	271.8×	0.006	PYCR1
hair follicle morphogenesis	1	247.8×	0.006	GORAB
positive regulation of smoothened signaling pathway	1	210.7×	0.006	GORAB
non-motile cilium assembly	1	145.3×	0.008	GORAB
cellular response to oxidative stress	1	77.3×	0.013	PYCR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
PYCR1	PARGYLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PYCR1	1	4
GORAB	0	0
GORAB-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PARGYLINE	4	PYCR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PYCR1	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PYCR1	1.5.1.2	pyrroline-5-carboxylate reductase

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

1 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)
PARGYLINE	4	PYCR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PYCR1
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	2	GORAB, GORAB-AS1

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)
GORAB	0	PYCR1
GORAB-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.