Meckel syndrome, type 10

Summary

Meckel syndrome, type 10 (MONDO:0013609) is a disease caused by B9D2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: B9D2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 10
Mondo ID	MONDO:0013609
OMIM	614175
UMLS	C3280036
MedGen	481666
GARD	0024937
Is cancer (heuristic)	no

Also known as: B9D2 Meckel syndrome · JBTS34 · Joubert syndrome 34 · meckel syndrome 10 · Meckel syndrome caused by mutation in B9D2 · Meckel syndrome, type 10 · MKS10

Data availability: 15 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 10

Related subtypes (13): Meckel syndrome, type 1, NPHP3-related Meckel-like syndrome, Meckel syndrome, type 2, Meckel syndrome, type 3, Meckel syndrome, type 4, Meckel syndrome, type 5, Meckel syndrome, type 6, Meckel syndrome, type 8, Meckel syndrome, type 9, Meckel syndrome, type 11, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, meckel syndrome 14, Meckel syndrome 13

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

15 retrieved; paginated sample, class counts are floors:

6 benign, 4 uncertain significance, 3 likely pathogenic, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30931	NM_030578.4(B9D2):c.301A>C (p.Ser101Arg)	B9D2	Pathogenic	criteria provided, single submitter
4531724	NM_030578.4(B9D2):c.127C>T (p.Gln43Ter)	B9D2	Likely pathogenic	criteria provided, single submitter
684427	NM_030578.4(B9D2):c.15C>A (p.His5Gln)	B9D2	Likely pathogenic	criteria provided, single submitter
812149	NM_030578.4(B9D2):c.168C>G (p.Tyr56Ter)	B9D2	Likely pathogenic	criteria provided, single submitter
1341710	NM_030578.4(B9D2):c.484G>T (p.Gly162Cys)	B9D2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2059724	NM_030578.4(B9D2):c.307C>T (p.Pro103Ser)	B9D2	Uncertain significance	criteria provided, multiple submitters, no conflicts
281470	NM_030578.4(B9D2):c.496C>T (p.Arg166Cys)	B9D2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3359110	NM_030578.4(B9D2):c.496C>G (p.Arg166Gly)	B9D2	Uncertain significance	criteria provided, single submitter
1192349	NM_030578.4(B9D2):c.214+25T>G	B9D2	Benign	criteria provided, multiple submitters, no conflicts
1192350	NM_030578.4(B9D2):c.-4-40C>G	B9D2	Benign	criteria provided, multiple submitters, no conflicts
1192351	NM_030578.4(B9D2):c.-4-60_-4-59insT	B9D2	Benign	criteria provided, multiple submitters, no conflicts
261879	NM_030578.4(B9D2):c.*18G>A	B9D2	Benign	criteria provided, multiple submitters, no conflicts
261881	NM_030578.4(B9D2):c.33A>G (p.Ile11Met)	B9D2	Benign	criteria provided, multiple submitters, no conflicts
261883	NM_030578.4(B9D2):c.88+6C>T	B9D2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
12534	NM_000660.7(TGFB1):c.29C>T (p.Pro10Leu)	TGFB1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 5 · 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
B9D2	Strong	Autosomal recessive	Meckel syndrome, type 10	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
B9D2	Orphanet:475	Isolated Joubert syndrome
B9D2	Orphanet:564	Meckel syndrome
TGFB1	Orphanet:1328	Camurati-Engelmann disease
TGFB1	Orphanet:565788	Infantile inflammatory bowel disease with neurological involvement
TGFB1	Orphanet:586	Cystic fibrosis

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
B9D2	HGNC:28636	ENSG00000123810	Q9BPU9	B9 domain-containing protein 2	gencc,clinvar
TGFB1	HGNC:11766	ENSG00000105329	P01137	Transforming growth factor beta-1 proprotein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
B9D2	B9 domain-containing protein 2	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
TGFB1	Transforming growth factor beta-1 proprotein	Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.

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)
B9D2	Other/Unknown	no		C2_B9-type_dom
TGFB1	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb1

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
blood	1
olfactory segment of nasal mucosa	1
right uterine tube	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
B9D2	138	ubiquitous	marker	right uterine tube, blood, olfactory segment of nasal mucosa
TGFB1	204	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFB1	7,596
B9D2	786

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFB1	P01137	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B9D2	Q9BPU9	89.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. 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
Influenza Virus Induced Apoptosis	1	2855.0×	0.008	TGFB1
TGFBR2 MSI Frameshift Mutants in Cancer	1	2855.0×	0.008	TGFB1
Loss of Function of TGFBR2 in Cancer	1	1903.3×	0.008	TGFB1
TGFBR2 Kinase Domain Mutants in Cancer	1	1903.3×	0.008	TGFB1
TGFBR1 LBD Mutants in Cancer	1	1427.5×	0.008	TGFB1
Loss of Function of TGFBR1 in Cancer	1	1142.0×	0.008	TGFB1
Loss of Function of SMAD2/3 in Cancer	1	951.7×	0.008	TGFB1
Signaling by TGF-beta Receptor Complex in Cancer	1	951.7×	0.008	TGFB1
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	951.7×	0.008	TGFB1
TGFBR1 KD Mutants in Cancer	1	951.7×	0.008	TGFB1
RUNX3 regulates CDKN1A transcription	1	815.7×	0.008	TGFB1
TGFBR3 regulates TGF-beta signaling	1	713.8×	0.008	TGFB1
RUNX3 regulates p14-ARF	1	571.0×	0.010	TGFB1
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)	1	335.9×	0.015	TGFB1
Syndecan interactions	1	211.5×	0.022	TGFB1
Downregulation of TGF-beta receptor signaling	1	203.9×	0.022	TGFB1
Signaling by TGFBR3	1	184.2×	0.023	TGFB1
Elastic fibre formation	1	167.9×	0.023	TGFB1
TGF-beta receptor signaling activates SMADs	1	163.1×	0.023	TGFB1
Molecules associated with elastic fibres	1	154.3×	0.023	TGFB1
Transcriptional regulation by RUNX3	1	135.9×	0.025	TGFB1
Regulation of RUNX3 expression and activity	1	116.5×	0.028	TGFB1
Signaling by TGF-beta Receptor Complex	1	100.2×	0.029	TGFB1
Amplification of signal from the kinetochores	1	98.5×	0.029	B9D2
Signal Transduction	2	10.2×	0.029	B9D2, TGFB1
Influenza Infection	1	87.8×	0.031	TGFB1
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.031	TGFB1
Mitotic Spindle Checkpoint	1	79.3×	0.031	B9D2
Adipogenesis	1	78.2×	0.031	TGFB1
Non-integrin membrane-ECM interactions	1	77.2×	0.031	TGFB1

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
columnar/cuboidal epithelial cell maturation	1	8426.0×	0.004	TGFB1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1	8426.0×	0.004	TGFB1
positive regulation of microglia differentiation	1	8426.0×	0.004	TGFB1
regulation of interleukin-23 production	1	8426.0×	0.004	TGFB1
branch elongation involved in mammary gland duct branching	1	8426.0×	0.004	TGFB1
embryonic liver development	1	4213.0×	0.004	TGFB1
positive regulation of primary miRNA processing	1	4213.0×	0.004	TGFB1
negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	1	2808.7×	0.004	TGFB1
regulation of blood vessel remodeling	1	2808.7×	0.004	TGFB1
frontal suture morphogenesis	1	2808.7×	0.004	TGFB1
regulation of enamel mineralization	1	2808.7×	0.004	TGFB1
tolerance induction to self antigen	1	2106.5×	0.004	TGFB1
positive regulation of exit from mitosis	1	2106.5×	0.004	TGFB1
response to laminar fluid shear stress	1	2106.5×	0.004	TGFB1
negative regulation of skeletal muscle tissue development	1	2106.5×	0.004	TGFB1
regulation of cartilage development	1	2106.5×	0.004	TGFB1
Langerhans cell differentiation	1	2106.5×	0.004	TGFB1
negative regulation of hyaluronan biosynthetic process	1	2106.5×	0.004	TGFB1
positive regulation of vasculature development	1	2106.5×	0.004	TGFB1
myofibroblast differentiation	1	1685.2×	0.004	TGFB1
regulation of protein import into nucleus	1	1685.2×	0.004	TGFB1
positive regulation of odontogenesis	1	1685.2×	0.004	TGFB1
negative regulation of release of sequestered calcium ion into cytosol	1	1685.2×	0.004	TGFB1
bronchiole development	1	1685.2×	0.004	TGFB1
regulation of branching involved in mammary gland duct morphogenesis	1	1685.2×	0.004	TGFB1
positive regulation of mononuclear cell migration	1	1685.2×	0.004	TGFB1
cellular response to acetaldehyde	1	1685.2×	0.004	TGFB1
connective tissue replacement involved in inflammatory response wound healing	1	1404.3×	0.004	TGFB1
negative regulation of extracellular matrix disassembly	1	1404.3×	0.004	TGFB1
regulation of striated muscle tissue development	1	1404.3×	0.004	TGFB1

Therapeutics

Drug target analysis

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

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
TGFB1	1	2
B9D2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VACTOSERTIB	2	TGFB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TGFB1	9	Binding:9

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

1 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)
VACTOSERTIB	2	TGFB1

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	1	TGFB1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	B9D2

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)
B9D2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.