multiple epiphyseal dysplasia, Al-Gazali type

Summary

multiple epiphyseal dysplasia, Al-Gazali type (MONDO:0011778) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 318
• Phenotypes (HPO): 22

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)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000207	Triangular mouth	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002419	Molar tooth sign on MRI	Very frequent (80-99%)
HP:0002654	Multiple epiphyseal dysplasia	Very frequent (80-99%)
HP:0002663	Delayed epiphyseal ossification	Very frequent (80-99%)
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0003037	Enlarged joints	Very frequent (80-99%)
HP:0030084	Clinodactyly	Very frequent (80-99%)
HP:0031092	Spindle-shaped finger	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0012725	Cutaneous syndactyly	Occasional (5-29%)
HP:0003468	Abnormal vertebral morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple epiphyseal dysplasia, Al-Gazali type
Mondo ID	MONDO:0011778
MeSH	C564621
OMIM	607131
Orphanet	166024
ICD-11	1359939784
SNOMED CT	719688002
UMLS	C1846722
MedGen	335505
GARD	0017014
Is cancer (heuristic)	no

Also known as: AGBK · multiple epiphyseal dysplasia-macrocephaly-distinctive facies syndrome

Data availability: 318 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › multiple epiphyseal dysplasia › multiple epiphyseal dysplasia, Al-Gazali type

Related subtypes (9): multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia, Beighton type, multiple epiphyseal dysplasia type 4, multiple epiphyseal dysplasia, Lowry type, multiple epiphyseal dysplasia type 5, multiple epiphyseal dysplasia, with severe proximal femoral dysplasia, multiple epiphyseal dysplasia, with miniepiphyses, multiple epiphyseal dysplasia due to collagen 9 anomaly, epiphyseal dysplasia, multiple, 7

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

318 retrieved; paginated sample, class counts are floors:

250 uncertain significance, 25 conflicting classifications of pathogenicity, 14 likely pathogenic, 12 benign, 9 pathogenic/likely pathogenic, 4 benign/likely benign, 3 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1201620	NM_198525.3(KIF7):c.1149dup (p.Ile384fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297573	NM_198525.3(KIF7):c.3235C>T (p.Gln1079Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380985	NM_198525.3(KIF7):c.1248del (p.Asp417fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454843	NM_198525.3(KIF7):c.2560_2570del (p.Ala854fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195441	NM_198525.3(KIF7):c.61C>T (p.Arg21Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264771	NM_198525.3(KIF7):c.3179A>G (p.Asn1060Ser)	KIF7	Pathogenic	no assertion criteria provided
3023369	NM_198525.3(KIF7):c.350_353dup (p.Ile119fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30895	NM_198525.3(KIF7):c.2896_2897del (p.Ala966fs)	KIF7	Pathogenic	criteria provided, multiple submitters, no conflicts
3891489	NM_198525.3(KIF7):c.2515C>T (p.Gln839Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520764	NM_198525.3(KIF7):c.328+2T>G	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587434	NM_198525.3(KIF7):c.67C>T (p.Arg23Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988539	NM_198525.3(KIF7):c.1019dup (p.Asn341fs)	KIF7	Pathogenic	criteria provided, multiple submitters, no conflicts
4278486	NM_001909.5(CTSD):c.972+1G>A	CTSD	Likely pathogenic	criteria provided, single submitter
1306220	NM_198525.3(KIF7):c.1443+2T>C	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2048811	NM_198525.3(KIF7):c.1789-2A>G	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578015	NM_198525.3(KIF7):c.3838_3886del (p.Ser1280fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578040	NM_198525.3(KIF7):c.3195C>A (p.Cys1065Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578060	NM_198525.3(KIF7):c.2869G>T (p.Glu957Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578062	NM_198525.3(KIF7):c.2758G>T (p.Glu920Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578063	NM_198525.3(KIF7):c.2718+1G>A	KIF7	Likely pathogenic	criteria provided, single submitter
3578066	NM_198525.3(KIF7):c.2618del (p.Gln873fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578092	NM_198525.3(KIF7):c.1703del (p.Leu568fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578109	NM_198525.3(KIF7):c.1295_1307dup (p.Lys439fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578124	NM_198525.3(KIF7):c.923+2T>G	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578129	NM_198525.3(KIF7):c.719_720insT (p.Gln242fs)	KIF7	Likely pathogenic	criteria provided, single submitter
4845879	NM_198525.3(KIF7):c.417_420del (p.Cys139fs)	KIF7	Likely pathogenic	criteria provided, single submitter
1024840	NM_198525.3(KIF7):c.50G>A (p.Arg17Gln)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1119022	NM_198525.3(KIF7):c.329-26_329-13del	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401610	NM_198525.3(KIF7):c.2345G>A (p.Arg782Gln)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1624285	NM_198525.3(KIF7):c.2896-9T>C	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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
KIF7	Supportive	Autosomal recessive	multiple epiphyseal dysplasia, Al-Gazali type	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF7	Orphanet:166024	Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome
KIF7	Orphanet:2189	Hydrolethalus
KIF7	Orphanet:2754	Orofaciodigital syndrome type 6
KIF7	Orphanet:36	Acrocallosal syndrome
CTSD	Orphanet:700487	Congenital CLN10 disease
CTSD	Orphanet:700492	Late infantile CLN10 disease
CTSD	Orphanet:700497	Juvenile CLN10 disease

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
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	gencc,clinvar
CTSD	HGNC:2529	ENSG00000117984	P07339	Cathepsin D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF7	Kinesin-like protein KIF7	Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms.
CTSD	Cathepsin D	Acid protease active in intracellular protein breakdown.

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
CTSD	Protease	yes	3.4.23.5	Aspartic_peptidase_A1, Aspartic_peptidase_AS, Aspartic_peptidase_N

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF7	165	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
CTSD	290	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTSD	4,280
KIF7	1,655

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTSD	P07339	9
KIF7	Q2M1P5	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Signaling by Insulin receptor	1	439.2×	0.029	CTSD
Metabolism of Angiotensinogen to Angiotensins	1	317.2×	0.029	CTSD
Insulin receptor recycling	1	190.3×	0.029	CTSD
Peptide hormone metabolism	1	135.9×	0.029	CTSD
Signaling by Hedgehog	1	92.1×	0.029	KIF7
Hedgehog ‘off’ state	1	89.2×	0.029	KIF7
Collagen degradation	1	87.8×	0.029	CTSD
Hedgehog ‘on’ state	1	79.3×	0.029	KIF7
Signal Transduction	2	10.2×	0.029	KIF7, CTSD
ESR-mediated signaling	1	64.2×	0.032	CTSD
Degradation of the extracellular matrix	1	58.9×	0.032	CTSD
Signaling by Nuclear Receptors	1	51.0×	0.034	CTSD
MHC class II antigen presentation	1	44.6×	0.036	CTSD
Estrogen-dependent gene expression	1	37.8×	0.039	CTSD
Extracellular matrix organization	1	31.6×	0.044	CTSD
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.050	CTSD
Adaptive Immune System	1	14.9×	0.081	CTSD
Innate Immune System	1	12.8×	0.090	CTSD
Neutrophil degranulation	1	11.5×	0.094	CTSD
Immune System	1	6.5×	0.155	CTSD
Metabolism of proteins	1	6.2×	0.155	CTSD

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
insulin receptor recycling	1	2106.5×	0.002	CTSD
insulin catabolic process	1	2106.5×	0.002	CTSD
lipoprotein catabolic process	1	1203.7×	0.002	CTSD
regulation of establishment of protein localization	1	1203.7×	0.002	CTSD
execution phase of apoptosis	1	383.0×	0.006	CTSD
antigen processing and presentation of exogenous peptide antigen via MHC class II	1	271.8×	0.007	CTSD
negative regulation of smoothened signaling pathway	1	227.7×	0.007	KIF7
positive regulation of smoothened signaling pathway	1	210.7×	0.007	KIF7
microtubule-based movement	1	147.8×	0.009	KIF7
autophagosome assembly	1	112.3×	0.011	CTSD
positive regulation of apoptotic process	1	28.4×	0.038	CTSD
proteolysis	1	17.1×	0.058	CTSD

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
CTSD	AMPRENAVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTSD	8	4
KIF7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
MOLIBRESIB	2	CTSD
URSOLIC ACID	2	CTSD
PEPSTATIN	2	CTSD
BALICATIB	2	CTSD
PIPERINE	2	CTSD
LY-2811376	1	CTSD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTSD	352	Binding:331, ADMET:15, Toxicity:3, Functional:3
KIF7	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTSD	3.4.23.5	cathepsin D

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CTSD	352

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

8 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)
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
MOLIBRESIB	2	CTSD
URSOLIC ACID	2	CTSD
PEPSTATIN	2	CTSD
BALICATIB	2	CTSD
PIPERINE	2	CTSD
LY-2811376	1	CTSD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTSD
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	KIF7

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)
KIF7	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.