Leber congenital amaurosis with early-onset deafness

Summary

Leber congenital amaurosis with early-onset deafness (MONDO:0060650) is a disease caused by TUBB4B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TUBB4B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis with early-onset deafness
Mondo ID	MONDO:0060650
OMIM	617879
DOID	DOID:0112240
UMLS	C4693498
MedGen	1646810
GARD	0026002
Is cancer (heuristic)	no

Also known as: LCAEOD · Leber congenital amaurosis with early-onset deafness

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Leber congenital amaurosis › Leber congenital amaurosis with early-onset deafness

Related subtypes (20): retinal aplasia, Leber congenital amaurosis 1, Leber congenital amaurosis 2, Leber congenital amaurosis 3, Leber congenital amaurosis 4, Leber congenital amaurosis 5, Leber congenital amaurosis 9, Leber congenital amaurosis 12, Leber congenital amaurosis 10, Leber congenital amaurosis 13, Leber congenital amaurosis 14, Leber congenital amaurosis 6, Leber congenital amaurosis 7, Leber congenital amaurosis 8, Leber congenital amaurosis 11, Leber congenital amaurosis 15, Leber congenital amaurosis 16, Leber congenital amaurosis 17, Leber congenital amaurosis 19, Leber congenital amaurosis 18

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

7 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
492938	NM_006088.6(TUBB4B):c.1172G>A (p.Arg391His)	TUBB4B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492939	NM_006088.6(TUBB4B):c.1171C>T (p.Arg391Cys)	TUBB4B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342143	NM_006088.6(TUBB4B):c.1072C>T (p.Pro358Ser)	TUBB4B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3069148	NM_006088.6(TUBB4B):c.1169G>A (p.Arg390Gln)	TUBB4B	Uncertain significance	criteria provided, single submitter
3069149	NM_006088.6(TUBB4B):c.1168C>T (p.Arg390Trp)	TUBB4B	Uncertain significance	criteria provided, single submitter
3069150	NM_006088.6(TUBB4B):c.928T>C (p.Tyr310His)	TUBB4B	Uncertain significance	criteria provided, single submitter
931932	NM_006088.6(TUBB4B):c.587_588del (p.Thr196fs)	TUBB4B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
TUBB4B	Strong	Autosomal dominant	Leber congenital amaurosis with early-onset deafness	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB4B	Orphanet:65	Leber congenital amaurosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TUBB4B	HGNC:20771	ENSG00000188229	P68371	Tubulin beta-4B chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB4B	Tubulin beta-4B chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB4B	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB4B	295	ubiquitous	marker	left testis, right testis, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB4B	1,158

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB4B	P68371	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 95. Enrichment computed across 1 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.016	TUBB4B
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB4B
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB4B
Gap junction trafficking	1	475.8×	0.016	TUBB4B
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB4B
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB4B
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB4B
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB4B
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB4B
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB4B
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB4B
HCMV Infection	1	326.3×	0.016	TUBB4B
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB4B
Gap junction assembly	1	292.8×	0.016	TUBB4B
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB4B
Selective autophagy	1	278.5×	0.016	TUBB4B
Protein folding	1	259.6×	0.016	TUBB4B
Centrosome maturation	1	253.8×	0.016	TUBB4B
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB4B
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB4B
Aggrephagy	1	248.3×	0.016	TUBB4B
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB4B
Recycling pathway of L1	1	223.9×	0.016	TUBB4B
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB4B
Post NMDA receptor activation events	1	203.9×	0.016	TUBB4B
Intraflagellar transport	1	200.3×	0.016	TUBB4B
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB4B
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB4B
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB4B
Signaling by Hedgehog	1	184.2×	0.016	TUBB4B

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
natural killer cell mediated cytotoxicity	1	432.1×	0.009	TUBB4B
mitotic cell cycle	1	133.8×	0.009	TUBB4B
microtubule cytoskeleton organization	1	121.2×	0.009	TUBB4B
flagellated sperm motility	1	117.0×	0.009	TUBB4B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TUBB4B	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB4B	22	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB4B
VINBLASTINE	4	TUBB4B
LEVOFLOXACIN ANHYDROUS	4	TUBB4B
DOCETAXEL	4	TUBB4B
NOSCAPINE	4	TUBB4B
VINBLASTINE SULFATE	4	TUBB4B
PACLITAXEL	4	TUBB4B
LEVOFLOXACIN	4	TUBB4B
VINORELBINE	4	TUBB4B
TIRBANIBULIN	4	TUBB4B
PODOFILOX	4	TUBB4B
VINCRISTINE	4	TUBB4B
DOCETAXEL ANHYDROUS	4	TUBB4B
PATUPILONE	3	TUBB4B
MOLIBRESIB	2	TUBB4B
ABT-751	2	TUBB4B
MAYTANSINE	2	TUBB4B
DOLASTATIN-10	2	TUBB4B
INDIBULIN	2	TUBB4B
PARBENDAZOLE	2	TUBB4B
NOCODAZOLE	2	TUBB4B
COMBRETASTATIN	1	TUBB4B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB4B	1,769	Binding:1726, Functional:37, ADMET:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB4B	1,769

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

22 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)
COLCHICINE	4	TUBB4B
VINBLASTINE	4	TUBB4B
LEVOFLOXACIN ANHYDROUS	4	TUBB4B
DOCETAXEL	4	TUBB4B
NOSCAPINE	4	TUBB4B
VINBLASTINE SULFATE	4	TUBB4B
PACLITAXEL	4	TUBB4B
LEVOFLOXACIN	4	TUBB4B
VINORELBINE	4	TUBB4B
TIRBANIBULIN	4	TUBB4B
PODOFILOX	4	TUBB4B
VINCRISTINE	4	TUBB4B
DOCETAXEL ANHYDROUS	4	TUBB4B
PATUPILONE	3	TUBB4B
MOLIBRESIB	2	TUBB4B
ABT-751	2	TUBB4B
MAYTANSINE	2	TUBB4B
DOLASTATIN-10	2	TUBB4B
INDIBULIN	2	TUBB4B
PARBENDAZOLE	2	TUBB4B
NOCODAZOLE	2	TUBB4B
COMBRETASTATIN	1	TUBB4B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB4B
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.