Brachyolmia-amelogenesis imperfecta syndrome

Summary

Brachyolmia-amelogenesis imperfecta syndrome (MONDO:0011018) is a disease caused by LTBP3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LTBP3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,517

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	brachyolmia-amelogenesis imperfecta syndrome
Mondo ID	MONDO:0011018
OMIM	601216
Orphanet	2899
DOID	DOID:0090143
SNOMED CT	716195006
UMLS	C1832594
MedGen	318659
GARD	0005478
Is cancer (heuristic)	no

Also known as: amelogenesis imperfecta and platyspondyly · DASS · dental anomalies and short stature · platyspondyly with amelogenesis imperfecta · platyspondyly-amelogenesis imperfecta syndrome · skeletal dysplasia with amelogenesis imperfecta and platyspondyly · tooth agenesis, selective, 6 · Verloes Bourguignon syndrome · Verloes-Bourguignon syndrome

Data availability: 1,517 ClinVar variants · 4 GenCC gene-disease records.

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 › spondyloepiphyseal dysplasia › brachyolmia-amelogenesis imperfecta syndrome

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, progressive pseudorheumatoid arthropathy of childhood, otospondylomegaepiphyseal dysplasia, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, X-linked spondyloepimetaphyseal dysplasia, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Kimberley type, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, immunoskeletal dysplasia with neurodevelopmental abnormalities, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling type

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:

280 uncertain significance, 255 likely benign, 22 pathogenic, 19 benign, 11 likely pathogenic, 8 conflicting classifications of pathogenicity, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455544	NM_001130144.3(LTBP3):c.3213_3214del (p.Gln1072fs)	LOC121832793	Pathogenic	criteria provided, single submitter
1351824	NM_001130144.3(LTBP3):c.3342dup (p.Gly1115fs)	LOC130006027	Pathogenic	criteria provided, multiple submitters, no conflicts
1412679	NM_001130144.3(LTBP3):c.1937del (p.Gly646fs)	LOC130006032	Pathogenic	criteria provided, single submitter
1327507	NM_001130144.3(LTBP3):c.1721-2A>G	LTBP3	Pathogenic	criteria provided, single submitter
1387276	NM_001130144.3(LTBP3):c.536_537del (p.Val179fs)	LTBP3	Pathogenic	criteria provided, single submitter
1417406	NM_001130144.3(LTBP3):c.1735C>T (p.Arg579Ter)	LTBP3	Pathogenic	criteria provided, single submitter
1441073	NM_001130144.3(LTBP3):c.932G>A (p.Trp311Ter)	LTBP3	Pathogenic	criteria provided, single submitter
1445505	NM_001130144.3(LTBP3):c.2542dup (p.Tyr848fs)	LTBP3	Pathogenic	criteria provided, single submitter
1452054	NM_001130144.3(LTBP3):c.1160_1161insGTGT (p.Gly388fs)	LTBP3	Pathogenic	criteria provided, single submitter
1722765	NM_001130144.3(LTBP3):c.3629-1G>T	LTBP3	Pathogenic	no assertion criteria provided
1950571	NM_001130144.3(LTBP3):c.1854_1860dup (p.Glu621fs)	LTBP3	Pathogenic	criteria provided, single submitter
2005613	NM_001130144.3(LTBP3):c.2821G>T (p.Glu941Ter)	LTBP3	Pathogenic	criteria provided, single submitter
2009579	NM_001130144.3(LTBP3):c.1483del (p.Glu495fs)	LTBP3	Pathogenic	criteria provided, single submitter
2022494	NM_001130144.3(LTBP3):c.1569del (p.Val524fs)	LTBP3	Pathogenic	criteria provided, single submitter
2026372	NM_001130144.3(LTBP3):c.2553_2554del (p.Cys852fs)	LTBP3	Pathogenic	criteria provided, single submitter
2035901	NM_001130144.3(LTBP3):c.3615dup (p.Lys1206fs)	LTBP3	Pathogenic	criteria provided, single submitter
204492	NM_001130144.3(LTBP3):c.1859dup (p.Cys620fs)	LTBP3	Pathogenic	no assertion criteria provided
204493	NM_001130144.3(LTBP3):c.2071_2084del (p.Tyr691fs)	LTBP3	Pathogenic	no assertion criteria provided
204494	NM_001130144.3(LTBP3):c.421C>T (p.Gln141Ter)	LTBP3	Pathogenic	no assertion criteria provided
204495	NM_001130144.3(LTBP3):c.1531+1G>T	LTBP3	Pathogenic	no assertion criteria provided
204496	NM_001130144.3(LTBP3):c.2216del (p.Gly739fs)	LTBP3	Pathogenic	criteria provided, single submitter
204497	NM_001130144.3(LTBP3):c.2356del (p.Val786fs)	LTBP3	Pathogenic	no assertion criteria provided
1067470	NM_001130144.3(LTBP3):c.2893+1G>T	LTBP3	Likely pathogenic	criteria provided, single submitter
1469895	NM_001130144.3(LTBP3):c.1979-1G>C	LTBP3	Likely pathogenic	criteria provided, single submitter
1470100	NM_001130144.3(LTBP3):c.1063+1G>A	LTBP3	Likely pathogenic	criteria provided, single submitter
1488229	NM_001130144.3(LTBP3):c.3628+2T>C	LTBP3	Likely pathogenic	criteria provided, single submitter
1523524	NM_001130144.3(LTBP3):c.1721-1G>A	LTBP3	Likely pathogenic	criteria provided, single submitter
1695908	NM_001130144.3(LTBP3):c.2495del (p.Phe832fs)	LTBP3	Likely pathogenic	no assertion criteria provided
1938182	NM_001130144.3(LTBP3):c.1720+1dup	LTBP3	Likely pathogenic	criteria provided, single submitter
1983373	NM_001130144.3(LTBP3):c.1531+1G>A	LTBP3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · 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
LTBP2	Definitive	Autosomal recessive	brachyolmia-amelogenesis imperfecta syndrome	20
LTBP3	Definitive	Autosomal recessive	brachyolmia-amelogenesis imperfecta syndrome	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
LTBP3	Orphanet:2623	Geleophysic dysplasia
LTBP3	Orphanet:2899	Brachyolmia-amelogenesis imperfecta syndrome
LTBP3	Orphanet:969	Acromicric dysplasia
SCYL1	Orphanet:466794	Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gencc,clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	gencc,clinvar
SCYL1	HGNC:14372	ENSG00000142186	Q96KG9	N-terminal kinase-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.
SCYL1	N-terminal kinase-like protein	Regulates COPI-mediated retrograde protein traffic at the interface between the Golgi apparatus and the endoplasmic reticulum.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
SCYL1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, ARM-like

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2
apex of heart	1
hindlimb stylopod muscle	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta
SCYL1	246	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBP2	2,658
LTBP3	2,339
SCYL1	1,334

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCYL1	Q96KG9	76.40
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Elastic fibre formation	2	335.9×	2e-05	LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	326.3×	2e-05	LTBP2, LTBP3
Molecules associated with elastic fibres	2	308.6×	2e-05	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	200.3×	4e-05	LTBP2, LTBP3
Signaling by TGFB family members	2	115.3×	1e-04	LTBP2, LTBP3
Extracellular matrix organization	2	63.1×	3e-04	LTBP2, LTBP3
Signal Transduction	2	10.2×	0.010	LTBP2, LTBP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transforming growth factor beta receptor signaling pathway	2	106.0×	0.002	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	802.5×	0.007	LTBP3
lung saccule development	1	702.2×	0.007	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	702.2×	0.007	LTBP3
supramolecular fiber organization	1	351.1×	0.007	LTBP2
positive regulation of bone resorption	1	330.4×	0.007	LTBP3
spinal cord motor neuron differentiation	1	312.1×	0.007	SCYL1
negative regulation of bone mineralization	1	312.1×	0.007	LTBP3
bone remodeling	1	312.1×	0.007	LTBP3
negative regulation of chondrocyte differentiation	1	224.7×	0.008	LTBP3
bone morphogenesis	1	200.6×	0.009	LTBP3
protein targeting	1	122.1×	0.013	LTBP2
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	112.3×	0.013	SCYL1
chondrocyte differentiation	1	100.3×	0.013	LTBP3
bone mineralization	1	90.6×	0.013	LTBP3
protein secretion	1	87.8×	0.013	LTBP2
neuron development	1	85.1×	0.013	SCYL1
intracellular protein localization	1	34.9×	0.030	SCYL1
inflammatory response	1	12.6×	0.077	SCYL1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
LTBP2	0	0
LTBP3	0	0
SCYL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	SCYL1
E	Difficult family or no structure, no drug	2	LTBP2, LTBP3

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LTBP2	0	—
LTBP3	0	—
SCYL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.