microcephalic osteodysplastic dysplasia, Saul-Wilson type

Summary

microcephalic osteodysplastic dysplasia, Saul-Wilson type (MONDO:0019407) is a disease caused by COG4 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COG4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26
• Phenotypes (HPO): 16
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000444	Convex nasal ridge	Very frequent (80-99%)
HP:0000446	Narrow nasal bridge	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001762	Talipes equinovarus	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0003311	Hypoplasia of the odontoid process	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004582	Irregularity of vertebral bodies	Very frequent (80-99%)
HP:0010230	Cone-shaped epiphyses of the phalanges of the hand	Very frequent (80-99%)
HP:0011833	Overhanging nasal tip	Very frequent (80-99%)
HP:0200055	Small hand	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephalic osteodysplastic dysplasia, Saul-Wilson type
Mondo ID	MONDO:0019407
OMIM	618150
Orphanet	85172
DOID	DOID:0111673
ICD-11	738688839
UMLS	C4509877
MedGen	1375647
GARD	0016736
Is cancer (heuristic)	no

Also known as: microcephalic osteodysplastic dysplasia · microcephalic osteodysplastic dysplasia, Saul-Wilson type · Saul-Wilson syndrome · SWILS

Data availability: 26 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 › autosomal genetic disease › autosomal dominant disease › microcephalic osteodysplastic dysplasia, Saul-Wilson type

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

26 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 benign, 4 likely pathogenic, 3 pathogenic, 1 likely benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
449730	NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)	COG4	Pathogenic	criteria provided, multiple submitters, no conflicts
585271	NM_015386.3(COG4):c.1546G>C (p.Gly516Arg)	COG4	Pathogenic	no assertion criteria provided
599648	NM_015386.3(COG4):c.1840G>T (p.Glu614Ter)	COG4	Pathogenic	criteria provided, multiple submitters, no conflicts
915303	NM_015386.3(COG4):c.73G>T (p.Gly25Ter)	COG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065305	NM_015386.3(COG4):c.1002+1G>T	COG4	Likely pathogenic	criteria provided, single submitter
3065319	NM_015386.3(COG4):c.2006C>T (p.Ala669Val)	COG4	Likely pathogenic	criteria provided, single submitter
3377650	NM_015386.3(COG4):c.433G>T (p.Gly145Ter)	COG4	Likely pathogenic	criteria provided, single submitter
3581232	NM_015386.3(COG4):c.1290C>A (p.Tyr430Ter)	COG4	Likely pathogenic	criteria provided, single submitter
582178	NM_015386.3(COG4):c.539A>G (p.Lys180Arg)	COG4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077174	NM_015386.3(COG4):c.373C>T (p.Arg125Cys)	COG4	Uncertain significance	criteria provided, single submitter
1326920	NM_015386.3(COG4):c.490C>T (p.Arg164Cys)	COG4	Uncertain significance	criteria provided, single submitter
1341707	NM_015386.3(COG4):c.2026T>C (p.Tyr676His)	COG4	Uncertain significance	criteria provided, single submitter
1360641	NM_015386.3(COG4):c.35C>T (p.Pro12Leu)	COG4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1804253	NM_015386.3(COG4):c.2095A>G (p.Thr699Ala)	COG4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1804352	NM_015386.3(COG4):c.1948G>C (p.Asp650His)	COG4	Uncertain significance	criteria provided, single submitter
320370	NM_015386.3(COG4):c.1631C>T (p.Ala544Val)	COG4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3393190	NM_015386.3(COG4):c.2339G>T (p.Arg780Leu)	COG4	Uncertain significance	criteria provided, single submitter
3581233	NM_015386.3(COG4):c.494A>G (p.Tyr165Cys)	COG4	Uncertain significance	criteria provided, single submitter
4277632	NM_015386.3(COG4):c.2162C>T (p.Thr721Met)	COG4	Uncertain significance	criteria provided, single submitter
992777	NM_015386.3(COG4):c.101C>T (p.Ala34Val)	COG4	Uncertain significance	criteria provided, single submitter
1179913	NM_015386.3(COG4):c.1482-25T>C	COG4	Benign	criteria provided, multiple submitters, no conflicts
128810	NM_015386.3(COG4):c.2142G>A (p.Ser714=)	COG4	Benign	criteria provided, multiple submitters, no conflicts
1590864	NM_015386.3(COG4):c.811A>G (p.Ile271Val)	COG4	Likely benign	criteria provided, multiple submitters, no conflicts
380088	NM_015386.3(COG4):c.845-18T>C	COG4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
95697	NM_015386.3(COG4):c.485C>T (p.Thr162Ile)	COG4	Benign	criteria provided, multiple submitters, no conflicts
95699	NM_015386.3(COG4):c.646C>T (p.Leu216=)	COG4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
COG4	Strong	Autosomal dominant	microcephalic osteodysplastic dysplasia, Saul-Wilson type	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COG4	Orphanet:263501	COG4-CDG
COG4	Orphanet:85172	Microcephalic osteodysplastic dysplasia, Saul-Wilson type

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
COG4	HGNC:18620	ENSG00000103051	Q9H9E3	Conserved oligomeric Golgi complex subunit 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COG4	Conserved oligomeric Golgi complex subunit 4	Required for normal Golgi function.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COG4	Other/Unknown	no		COG4_M, COG4_N, COG4

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
apex of heart	1
lower esophagus mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COG4	273	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COG4	1,452

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COG4	Q9H9E3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Intra-Golgi traffic	1	259.6×	0.007	COG4
Retrograde transport at the Trans-Golgi-Network	1	219.6×	0.007	COG4
COPI-mediated anterograde transport	1	109.8×	0.009	COG4

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
retrograde transport, vesicle recycling within Golgi	1	1872.4×	0.002	COG4
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	337.0×	0.006	COG4
Golgi organization	1	133.8×	0.010	COG4
protein transport	1	43.9×	0.023	COG4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COG4	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
COG4	2	Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	COG4

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)
COG4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry