Cataract 5 multiple types

Summary

Cataract 5 multiple types (MONDO:0007290) is a disease caused by HSF4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: HSF4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract 5 multiple types
Mondo ID	MONDO:0007290
MeSH	C535342
OMIM	116800
DOID	DOID:0110255
UMLS	C0266537
MedGen	78608
GARD	0024547
Is cancer (heuristic)	no

Also known as: cataract (disease) caused by mutation in HSF4 · cataract 5, multiple types · CTRCT5 · HSF4 cataract (disease)

Data availability: 122 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › cataract › early-onset non-syndromic cataract › cataract 5 multiple types

Related subtypes (28): cataract 32 multiple types, cataract 8 multiple types, cataract 42, cataract 20 multiple types, cataract 6 multiple types, cataract 13 with adult I phenotype, cataract 46 juvenile-onset, cataract 40, cataract 10 multiple types, cataract 14 multiple types, pulverulent cataract, cataract 31 multiple types, cataract 26 multiple types, cataract 22 multiple types, cataract 21 multiple types, cataract 23, cataract 11 multiple types, cataract 33, cataract 17 multiple types, cataract 38, cataract 39 multiple types, cataract 15 multiple types, cataract 19 multiple types, cataract 43, cataract 44, cataract 45, early-onset partial cataract, total early-onset cataract

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

122 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 20 likely benign, 15 benign, 14 pathogenic, 7 benign/likely benign, 7 conflicting classifications of pathogenicity, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424194	NC_000016.9:g.(?65821800)(67208957_?)del	B3GNT9	Pathogenic	criteria provided, single submitter
1333484	NM_001374675.1(HSF4):c.392G>A (p.Trp131Ter)	HSF4	Pathogenic	criteria provided, single submitter
1995440	NM_001374675.1(HSF4):c.568C>T (p.Gln190Ter)	HSF4	Pathogenic	criteria provided, single submitter
2137837	NM_001374675.1(HSF4):c.69G>T (p.Lys23Asn)	HSF4	Pathogenic	criteria provided, single submitter
2431622	NM_001374675.1(HSF4):c.627-2A>G	HSF4	Pathogenic	criteria provided, single submitter
3376746	NM_001374675.1(HSF4):c.1213C>T (p.Arg405Ter)	HSF4	Pathogenic	criteria provided, single submitter
3544405	NM_001374675.1(HSF4):c.1273dup (p.Glu425fs)	HSF4	Pathogenic	criteria provided, single submitter
3696447	NM_001374675.1(HSF4):c.536dup (p.Gln180fs)	HSF4	Pathogenic	criteria provided, single submitter
459609	NM_001374675.1(HSF4):c.89del (p.Asp30fs)	HSF4	Pathogenic	criteria provided, single submitter
567423	NM_001374675.1(HSF4):c.965dup (p.Pro323fs)	HSF4	Pathogenic	criteria provided, multiple submitters, no conflicts
7092	NM_001374675.1(HSF4):c.341T>C (p.Leu114Pro)	HSF4	Pathogenic	no assertion criteria provided
7093	NM_001374675.1(HSF4):c.355C>T (p.Arg119Cys)	HSF4	Pathogenic	no assertion criteria provided
7094	NM_001374675.1(HSF4):c.56C>A (p.Ala19Asp)	HSF4	Pathogenic	no assertion criteria provided
7095	NM_001374675.1(HSF4):c.256A>G (p.Ile86Val)	HSF4	Pathogenic	no assertion criteria provided
3727898	NM_001374675.1(HSF4):c.117_123+3del	HSF4	Likely pathogenic	criteria provided, single submitter
4538472	NM_001374675.1(HSF4):c.897del (p.Asp302fs)	HSF4	Likely pathogenic	criteria provided, single submitter
459607	NM_001374675.1(HSF4):c.1255-2A>G	HSF4	Likely pathogenic	criteria provided, single submitter
582457	NM_001374675.1(HSF4):c.352C>T (p.Arg118Trp)	HSF4	Likely pathogenic	criteria provided, single submitter
320179	NM_001374675.1(HSF4):c.259G>A (p.Glu87Lys)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320180	NM_001374675.1(HSF4):c.394C>T (p.Arg132Cys)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320188	NM_001374675.1(HSF4):c.1127T>C (p.Leu376Pro)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522680	NM_001374675.1(HSF4):c.426_443dup (p.Ala145_Gln150dup)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885525	NM_001374675.1(HSF4):c.680C>A (p.Thr227Asn)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885527	NM_001374675.1(HSF4):c.991G>A (p.Ala331Thr)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886550	NM_001374675.1(HSF4):c.1315C>T (p.Pro439Ser)	HSF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320166	NM_001538.3(HSF4):c.-759A>G	FBXL8	Uncertain significance	criteria provided, single submitter
320169	NM_001538.4(HSF4):c.-448A>G	FBXL8	Uncertain significance	criteria provided, single submitter
884526	NM_018378.3(FBXL8):c.720A>C (p.Glu240Asp)	FBXL8	Uncertain significance	criteria provided, multiple submitters, no conflicts
885460	NM_001538.3(HSF4):c.-874G>C	FBXL8	Uncertain significance	criteria provided, single submitter
885461	NM_001538.3(HSF4):c.-833C>T	FBXL8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
HSF4	Definitive	Autosomal dominant	cataract 5 multiple types	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSF4	Orphanet:441452	Early-onset lamellar cataract
HSF4	Orphanet:98994	Total early-onset cataract

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
HSF4	HGNC:5227	ENSG00000102878	Q9ULV5	Heat shock factor protein 4	gencc,clinvar
FBXL8	HGNC:17875	ENSG00000135722	Q96CD0	F-box/LRR-repeat protein 8	clinvar
B3GNT9	HGNC:28714	ENSG00000237172	Q6UX72	UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSF4	Heat shock factor protein 4	Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE).
FBXL8	F-box/LRR-repeat protein 8	Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSF4	Other/Unknown	no		HSF_DNA-bd, WH-like_DNA-bd_sf, WH_DNA-bd_sf
FBXL8	Other/Unknown	no		F-box_dom, LRR_dom_sf, F-box-like_dom_sf
B3GNT9	Other/Unknown	no		Glyco_trans_31

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
body of pancreas	1
prostate gland	1
right uterine tube	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSF4	186	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FBXL8	139	ubiquitous	yes	body of pancreas, right uterine tube, prostate gland
B3GNT9	233	ubiquitous	marker	stromal cell of endometrium, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSF4	967
FBXL8	762
B3GNT9	456

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSF4	Q9ULV5	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXL8	Q96CD0	91.78
B3GNT9	Q6UX72	83.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
O-linked glycosylation of mucins	1	92.1×	0.041	B3GNT9
O-linked glycosylation	1	72.3×	0.041	B3GNT9
Neddylation	1	23.7×	0.080	FBXL8
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.080	FBXL8
Post-translational protein modification	1	9.6×	0.122	B3GNT9
Metabolism of proteins	1	6.2×	0.155	B3GNT9

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
poly-N-acetyllactosamine biosynthetic process	1	1053.2×	0.004	B3GNT9
lens fiber cell differentiation	1	526.6×	0.004	HSF4
protein O-linked glycosylation	1	112.3×	0.012	B3GNT9
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	HSF4

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
HSF4	0	0
FBXL8	0	0
B3GNT9	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
HSF4	1	Binding:1

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	HSF4, FBXL8, B3GNT9

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)
HSF4	1	—
FBXL8	0	—
B3GNT9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.