Bardet-Biedl syndrome 2

Summary

Bardet-Biedl syndrome 2 (MONDO:0014432) is a disease caused by BBS2 (GenCC Definitive), with 3 cohort genes and 17 clinical trials. Top therapeutic interventions include setmelanotide and metformin.

At a glance

• Causal gene: BBS2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 508
• Clinical trials: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bardet-Biedl syndrome 2
Mondo ID	MONDO:0014432
MeSH	C537910
OMIM	615981
DOID	DOID:0110124
UMLS	C2936863
MedGen	422453
GARD	0000821
Is cancer (heuristic)	no

Also known as: Bardet-Biedl syndrome · Bardet-Biedl syndrome 2 · Bardet-Biedl syndrome caused by mutation in BBS2 · Bardet-Biedl syndrome type 2 · BBS · BBS2 · BBS2 Bardet-Biedl syndrome

Data availability: 508 ClinVar variants · 5 GenCC gene-disease records · 81 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Bardet-Biedl syndrome › Bardet-Biedl syndrome 2

Related subtypes (21): Bardet-Biedl syndrome 1, Bardet-Biedl syndrome 3, Bardet-Biedl syndrome 6, Bardet-Biedl syndrome 4, Bardet-Biedl syndrome 5, Bardet-Biedl syndrome 7, Bardet-Biedl syndrome 8, Bardet-Biedl syndrome 9, Bardet-Biedl syndrome 10, Bardet-Biedl syndrome 11, Bardet-Biedl syndrome 12, Bardet-Biedl syndrome 13, Bardet-Biedl syndrome 14, Bardet-Biedl syndrome 15, Bardet-Biedl syndrome 16, Bardet-Biedl syndrome 17, Bardet-Biedl syndrome 18, Bardet-Biedl syndrome 19, Bardet-Biedl syndrome 22, Bardet-Biedl syndrome 20, bardet-biedl syndrome 21

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

508 retrieved; paginated sample, class counts are floors:

218 uncertain significance, 107 likely pathogenic, 53 pathogenic/likely pathogenic, 45 conflicting classifications of pathogenicity, 33 pathogenic, 32 likely benign, 11 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066989	NM_031885.5(BBS2):c.1397+1G>A	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069221	NM_031885.5(BBS2):c.326C>A (p.Ser109Ter)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069384	NM_031885.5(BBS2):c.1371del (p.Lys458fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070027	NM_031885.5(BBS2):c.613-1G>C	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071242	NM_031885.5(BBS2):c.437del (p.Gly146fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076595	NM_031885.5(BBS2):c.1649_1650del (p.Leu550fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210364	NM_031885.5(BBS2):c.1725del (p.Phe575fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339335	NM_031885.5(BBS2):c.1762_1765del (p.Val588fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367251	NM_031885.5(BBS2):c.256_278dup (p.Val94fs)	BBS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1378633	NM_031885.5(BBS2):c.255del (p.Glu86fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400662	NM_031885.5(BBS2):c.1932T>G (p.Tyr644Ter)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452448	NM_031885.5(BBS2):c.1161del (p.Ser388fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457122	NM_031885.5(BBS2):c.1662dup (p.Thr555fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193747	NM_031885.5(BBS2):c.1099dup (p.Leu367fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1962207	NM_031885.5(BBS2):c.1163C>A (p.Ser388Ter)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1986519	NM_031885.5(BBS2):c.79A>C (p.Thr27Pro)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2024001	NM_031885.5(BBS2):c.1997_1998del (p.Thr666fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208564	NM_031885.5(BBS2):c.661del (p.Leu221fs)	BBS2	Pathogenic	criteria provided, multiple submitters, no conflicts
209043	NM_031885.5(BBS2):c.401C>G (p.Pro134Arg)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2093277	NM_031885.5(BBS2):c.717+1G>T	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217434	NM_031885.5(BBS2):c.263del (p.Gly88fs)	BBS2	Pathogenic	criteria provided, multiple submitters, no conflicts
2680024	NM_031885.5(BBS2):c.1310_1344del (p.Leu437fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2740944	NM_031885.5(BBS2):c.1015del (p.Arg339fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
284737	NM_031885.5(BBS2):c.1864C>T (p.Arg622Ter)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30550	NM_031885.5(BBS2):c.472-2A>G	BBS2	Pathogenic	criteria provided, single submitter
3240882	NM_031885.5(BBS2):c.612+1G>A	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382258	NM_031885.5(BBS2):c.1059dup (p.Asn354Ter)	BBS2	Pathogenic	criteria provided, single submitter
35754	NM_031885.5(BBS2):c.1015C>T (p.Arg339Ter)	BBS2	Pathogenic	criteria provided, multiple submitters, no conflicts
35755	NM_031885.5(BBS2):c.1770del (p.Phe590fs)	BBS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370943	NM_031885.5(BBS2):c.1237C>T (p.Arg413Ter)	BBS2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 8 · 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
BBS2	Definitive	Autosomal recessive	Bardet-Biedl syndrome 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BBS2	Orphanet:110	Bardet-Biedl syndrome
BBS2	Orphanet:791	Retinitis pigmentosa
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
F8	Orphanet:169802	Severe hemophilia A
F8	Orphanet:169805	Moderate hemophilia A
F8	Orphanet:169808	Mild hemophilia A
F8	Orphanet:177926	Bleeding disorder in hemophilia A carriers

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
BBS2	HGNC:967	ENSG00000125124	Q9BXC9	BBSome complex member BBS2	gencc,clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	clinvar
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BBS2	BBSome complex member BBS2	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BBS2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, Bardet-Biedl_syndrome_2_prot, BBS2_GAE_dom
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf

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
adrenal tissue	1
peripheral nervous system	1
right adrenal gland cortex	1
calcaneal tendon	1
cerebellar hemisphere	1
right uterine tube	1
heart right ventricle	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BBS2	262	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, peripheral nervous system
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
F8	266	broad	marker	left ventricle myocardium, heart right ventricle, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F8	1,900
BBS2	1,824
TTC21B	1,588

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F8	P00451	25
TTC21B	Q7Z4L5	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BBS2	Q9BXC9	89.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective F8 accelerates dissociation of the A2 domain	1	3806.7×	0.002	F8
Defective F8 binding to the cell membrane	1	3806.7×	0.002	F8
Defective F8 secretion	1	3806.7×	0.002	F8
Defective F8 binding to von Willebrand factor	1	1903.3×	0.002	F8
Defective factor IX causes thrombophilia	1	1268.9×	0.002	F8
Defective F8 cleavage by thrombin	1	1268.9×	0.002	F8
Defective cofactor function of FVIIIa variant	1	1268.9×	0.002	F8
Defective F9 variant does not activate FX	1	1268.9×	0.002	F8
Defective F8 sulfation at Y1699	1	1268.9×	0.002	F8
Amplification and propagation of coagulation cascade	1	211.5×	0.010	F8
BBSome-mediated cargo-targeting to cilium	1	165.5×	0.012	BBS2
Initiation of coagulation cascade	1	158.6×	0.012	F8
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	141.0×	0.012	F8
Cargo concentration in the ER	1	112.0×	0.014	F8
Cargo trafficking to the periciliary membrane	1	82.8×	0.018	BBS2
Regulation of clotting cascade	1	77.7×	0.018	F8
Intraflagellar transport	1	66.8×	0.019	TTC21B
Hedgehog ‘off’ state	1	59.5×	0.020	TTC21B
COPII-mediated vesicle transport	1	54.4×	0.021	F8
Cilium Assembly	1	36.2×	0.030	BBS2
Platelet degranulation	1	29.3×	0.035	F8
Organelle biogenesis and maintenance	1	22.0×	0.045	BBS2

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
regulation of intraciliary retrograde transport	1	2808.7×	0.007	TTC21B
negative regulation of appetite by leptin-mediated signaling pathway	1	1404.3×	0.007	BBS2
protein localization to non-motile cilium	1	1404.3×	0.007	TTC21B
negative regulation of eating behavior	1	936.2×	0.007	TTC21B
blood coagulation, intrinsic pathway	1	702.2×	0.007	F8
forebrain dorsal/ventral pattern formation	1	702.2×	0.007	TTC21B
artery smooth muscle contraction	1	624.1×	0.007	BBS2
regulation of cilium beat frequency involved in ciliary motility	1	624.1×	0.007	BBS2
cilium assembly	2	49.1×	0.007	BBS2, TTC21B
Bergmann glial cell differentiation	1	510.7×	0.008	TTC21B
striatum development	1	374.5×	0.008	BBS2
intraciliary retrograde transport	1	374.5×	0.008	TTC21B
negative regulation of multicellular organism growth	1	374.5×	0.008	BBS2
cerebellar Purkinje cell differentiation	1	351.1×	0.008	TTC21B
ventricular system development	1	280.9×	0.009	TTC21B
melanosome transport	1	255.3×	0.010	BBS2
brain morphogenesis	1	244.2×	0.010	BBS2
regulation of smoothened signaling pathway	1	208.1×	0.011	TTC21B
Golgi to plasma membrane protein transport	1	175.5×	0.012	BBS2
positive regulation of multicellular organism growth	1	165.2×	0.012	BBS2
sperm axoneme assembly	1	156.0×	0.012	BBS2
adult behavior	1	156.0×	0.012	BBS2
acute-phase response	1	140.4×	0.012	F8
protein localization to cilium	1	133.8×	0.012	TTC21B
vasodilation	1	122.1×	0.013	BBS2
photoreceptor cell maintenance	1	119.5×	0.013	BBS2
non-motile cilium assembly	1	96.8×	0.015	BBS2
cartilage development	1	83.8×	0.017	BBS2
hippocampus development	1	77.0×	0.018	BBS2
cerebral cortex development	1	68.5×	0.019	BBS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BBS2	0	0
TTC21B	0	0
F8	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
F8	8	Binding:8

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	0
E	Difficult family or no structure, no drug	3	BBS2, TTC21B, F8

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)
BBS2	0	—
TTC21B	0	—
F8	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE3	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT02329210	Not specified	RECRUITING	Clinical Registry Investigating Bardet-Biedl Syndrome
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT04461444	Not specified	RECRUITING	COhort for Bardet-Bield Syndrome and Alström Syndrome for Translational Research Monocentric Interventional Study
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06615011	Not specified	NOT_YET_RECRUITING	Bardet Beidle Syndrome in a Syrian Adolescent : a Rare Case Report
NCT00078091	Not specified	TERMINATED	Genetics and Clinical Characteristics of Bardet-Biedl Syndrome
NCT00213811	Not specified	COMPLETED	Bardet-Biedl Syndrome Study: Clinical and Genetic Epidemiology Study in Adults
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05183802	Not specified	APPROVED_FOR_MARKETING	An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
NCT05400278	Not specified	COMPLETED	Characterizing the Genotype and Phenotype in Adults With Bardet-Biedl Syndrome
NCT07602803	Not specified	COMPLETED	The Effect of GLP1 Agonists on Weight Loss in BBS Cohort in the UK

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SETMELANOTIDE	4	4
METFORMIN	4	1
CHEMBL4067491	0	4