Bruck syndrome 1

Summary

Bruck syndrome 1 (MONDO:0009806) is a disease caused by FKBP10 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: FKBP10 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bruck syndrome 1
Mondo ID	MONDO:0009806
OMIM	259450
UMLS	C1850168
MedGen	342431
GARD	0024696
Is cancer (heuristic)	no

Also known as: arthrogryposis-like disorder · BRKS1 · Bruck syndrome 1 · Bruck syndrome caused by mutation in FKBP10 · Bruck syndrome type 1 · FKBP10 Bruck syndrome

Data availability: 36 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Bruck syndrome › Bruck syndrome 1

Related subtypes (1): Bruck syndrome 2

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

36 retrieved; paginated sample, class counts are floors:

10 pathogenic, 9 likely pathogenic, 8 pathogenic/likely pathogenic, 4 uncertain significance, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1490007	NM_021939.4(FKBP10):c.1621C>T (p.Gln541Ter)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687196	NM_021939.4(FKBP10):c.124G>T (p.Glu42Ter)	FKBP10	Pathogenic	criteria provided, single submitter
208427	NM_021939.4(FKBP10):c.877_879del (p.Tyr293del)	FKBP10	Pathogenic	criteria provided, multiple submitters, no conflicts
2880784	NM_021939.4(FKBP10):c.1563+1G>A	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910427	NM_021939.4(FKBP10):c.1276del (p.Gln426fs)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30631	NM_021939.4(FKBP10):c.1016_1023dup (p.Thr342fs)	FKBP10	Pathogenic	no assertion criteria provided
30633	NM_021939.4(FKBP10):c.1276dup (p.Gln426fs)	FKBP10	Pathogenic	criteria provided, multiple submitters, no conflicts
30634	NM_021939.4(FKBP10):c.344G>A (p.Arg115Gln)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30635	NM_021939.4(FKBP10):c.743dup (p.Gln249fs)	FKBP10	Pathogenic	criteria provided, multiple submitters, no conflicts
3581947	NM_021939.4(FKBP10):c.829_841del (p.Pro277fs)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3629941	NM_021939.4(FKBP10):c.1256+1G>A	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41425	NM_021939.4(FKBP10):c.1271_1272delinsA (p.Ala424fs)	FKBP10	Pathogenic	no assertion criteria provided
41473	NM_021939.4(FKBP10):c.337G>A (p.Glu113Lys)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4291905	NM_021939.4(FKBP10):c.21del (p.Ser8fs)	FKBP10	Pathogenic	criteria provided, single submitter
438659	NM_021939.4(FKBP10):c.831dup (p.Gly278fs)	FKBP10	Pathogenic	criteria provided, multiple submitters, no conflicts
4819323	NM_021939.4(FKBP10):c.987del (p.Leu330fs)	FKBP10	Pathogenic	criteria provided, single submitter
503914	NM_021939.4(FKBP10):c.831del (p.Gly278fs)	FKBP10	Pathogenic	criteria provided, multiple submitters, no conflicts
631496	NM_021939.4(FKBP10):c.890_897dup (p.Gly300Ter)	FKBP10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197451	NM_000089.4(COL1A2):c.2693G>T (p.Gly898Val)	COL1A2	Likely pathogenic	criteria provided, single submitter
1683709	NM_021939.4(FKBP10):c.179A>C (p.Gln60Pro)	FKBP10	Likely pathogenic	criteria provided, single submitter
2996999	NM_021939.4(FKBP10):c.727+2del	FKBP10	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581945	NM_021939.4(FKBP10):c.726T>G (p.Tyr242Ter)	FKBP10	Likely pathogenic	criteria provided, single submitter
3581946	NM_021939.4(FKBP10):c.743del (p.Pro248fs)	FKBP10	Likely pathogenic	criteria provided, single submitter
3581948	NM_021939.4(FKBP10):c.1400-1G>T	FKBP10	Likely pathogenic	criteria provided, single submitter
3581949	NM_021939.4(FKBP10):c.1499_1502dup (p.Ala503fs)	FKBP10	Likely pathogenic	criteria provided, single submitter
3581950	NM_021939.4(FKBP10):c.1564-2A>T	FKBP10	Likely pathogenic	criteria provided, single submitter
4819324	NM_021939.4(FKBP10):c.770_771delinsCA (p.Leu257Pro)	FKBP10	Likely pathogenic	criteria provided, single submitter
323183	NM_021939.4(FKBP10):c.520G>A (p.Gly174Ser)	FKBP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
764420	NM_021939.4(FKBP10):c.1256+8C>G	FKBP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1360202	NM_021939.4(FKBP10):c.1003A>G (p.Met335Val)	FKBP10	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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
FKBP10	Definitive	Autosomal recessive	Bruck syndrome 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FKBP10	Orphanet:1149	Kuskokwim syndrome
FKBP10	Orphanet:216812	Osteogenesis imperfecta type 3
FKBP10	Orphanet:216820	Osteogenesis imperfecta type 4
FKBP10	Orphanet:2771	Bruck syndrome
COL1A2	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A2	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A2	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A2	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A2	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A2	Orphanet:230851	Cardiac-valvular Ehlers-Danlos syndrome
COL1A2	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A2	Orphanet:314029	High bone mass osteogenesis imperfecta

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
FKBP10	HGNC:18169	ENSG00000141756	Q96AY3	Peptidyl-prolyl cis-trans isomerase FKBP10	gencc,clinvar
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FKBP10	Peptidyl-prolyl cis-trans isomerase FKBP10	PPIases accelerate the folding of proteins during protein synthesis.
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FKBP10	Other/Unknown	no		PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily

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
stromal cell of endometrium	2
ascending aorta	1
thoracic aorta	1
periodontal ligament	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FKBP10	179	ubiquitous	marker	stromal cell of endometrium, ascending aorta, thoracic aorta
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FKBP10	3,473
COL1A2	179

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A2	P08123	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FKBP10	Q96AY3	89.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. 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 VWF binding to collagen type I	1	3806.7×	0.003	COL1A2
Enhanced cleavage of VWF variant by ADAMTS13	1	2855.0×	0.003	COL1A2
Defective VWF cleavage by ADAMTS13 variant	1	2855.0×	0.003	COL1A2
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	1631.4×	0.003	COL1A2
Defective binding of VWF variant to GPIb:IX:V	1	1631.4×	0.003	COL1A2
GP1b-IX-V activation signalling	1	951.7×	0.004	COL1A2
Anchoring fibril formation	1	761.3×	0.004	COL1A2
Platelet Adhesion to exposed collagen	1	671.8×	0.004	COL1A2
Scavenging by Class A Receptors	1	601.0×	0.004	COL1A2
Fibronectin matrix formation	1	571.0×	0.004	COL1A2
Crosslinking of collagen fibrils	1	571.0×	0.004	COL1A2
Platelet Aggregation (Plug Formation)	1	439.2×	0.005	COL1A2
Syndecan interactions	1	423.0×	0.005	COL1A2
MET activates PTK2 signaling	1	380.7×	0.005	COL1A2
GPVI-mediated activation cascade	1	308.6×	0.005	COL1A2
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.005	COL1A2
Collagen chain trimerization	1	259.6×	0.006	COL1A2
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.007	COL1A2
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.007	COL1A2
Collagen degradation	1	175.7×	0.008	COL1A2
Collagen biosynthesis and modifying enzymes	1	170.4×	0.008	COL1A2
Non-integrin membrane-ECM interactions	1	154.3×	0.008	COL1A2
ECM proteoglycans	1	150.3×	0.008	COL1A2
Integrin cell surface interactions	1	134.3×	0.008	COL1A2
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.010	COL1A2
Cell surface interactions at the vascular wall	1	95.2×	0.011	COL1A2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.011	COL1A2

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
extracellular matrix assembly	2	936.2×	2e-05	FKBP10, COL1A2
collagen fibril organization	2	224.7×	2e-04	FKBP10, COL1A2
protein heterotrimerization	1	8426.0×	7e-04	COL1A2
skin morphogenesis	1	702.2×	0.006	COL1A2
collagen metabolic process	1	526.6×	0.006	COL1A2
aorta morphogenesis	1	443.5×	0.006	FKBP10
odontogenesis	1	263.3×	0.009	COL1A2
blood vessel development	1	187.2×	0.011	COL1A2
cellular response to amino acid stimulus	1	153.2×	0.012	COL1A2
bone mineralization	1	135.9×	0.012	COL1A2
Rho protein signal transduction	1	123.9×	0.012	COL1A2
wound healing	1	113.9×	0.012	FKBP10
regulation of blood pressure	1	110.9×	0.012	COL1A2
transforming growth factor beta receptor signaling pathway	1	79.5×	0.015	COL1A2
skeletal system development	1	62.9×	0.018	COL1A2
protein folding	1	51.7×	0.020	FKBP10
in utero embryonic development	1	36.0×	0.028	FKBP10

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
FKBP10	0	0
COL1A2	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
COL1A2	4	Functional:4

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FKBP10, COL1A2

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)
FKBP10	0	—
COL1A2	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.