Early-onset lamellar cataract

Summary

Early-onset lamellar cataract (MONDO:0018611) is a disease with 12 cohort genes.

At a glance

• Cohort genes: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset lamellar cataract
Mondo ID	MONDO:0018611
Orphanet	441452
UMLS	C5681191
MedGen	1843303
GARD	0013155
Is cancer (heuristic)	no

Data availability: 11 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › cataract › early-onset non-syndromic cataract › early-onset partial cataract › early-onset zonular cataract › cataract 16 multiple types › early-onset lamellar cataract

Related subtypes (1): early-onset posterior polar 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 100 · Orphanet: 43 · 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
BFSP2	Definitive	Autosomal dominant	cataract 12 multiple types	9
CRYAA	Definitive	Autosomal recessive	cataract 9 multiple types	8
CRYBA1	Definitive	Autosomal dominant	cataract 10 multiple types	7
CRYBA4	Definitive	Autosomal dominant	cataract 23	6
CRYGC	Definitive	Autosomal dominant	cataract 2, multiple types	7
CRYGD	Definitive	Autosomal dominant	cataract 4 multiple types	9
CRYGS	Definitive	Autosomal dominant	cataract 20 multiple types	5
HSF4	Definitive	Autosomal dominant	cataract 5 multiple types	7
MIP	Definitive	Autosomal dominant	cataract 15 multiple types	10
TNPO1	Definitive	Autosomal dominant	cataract 15 multiple types	11
CRYAB	Strong	Autosomal dominant	cataract 16 multiple types	16
CRYGB	Supportive	Autosomal dominant	early-onset lamellar cataract	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BFSP2	Orphanet:441452	Early-onset lamellar cataract
BFSP2	Orphanet:98984	Pulverulent cataract
BFSP2	Orphanet:98985	Early-onset sutural cataract
CRYAA	Orphanet:1377	Cataract-microcornea syndrome
CRYAA	Orphanet:441452	Early-onset lamellar cataract
CRYAA	Orphanet:98988	Early-onset anterior polar cataract
CRYAA	Orphanet:98991	Early-onset nuclear cataract
CRYAA	Orphanet:98994	Total early-onset cataract
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract
CRYBA1	Orphanet:441452	Early-onset lamellar cataract
CRYBA1	Orphanet:98985	Early-onset sutural cataract
CRYBA1	Orphanet:98991	Early-onset nuclear cataract
CRYBA1	Orphanet:98993	Early-onset posterior polar cataract
CRYBA4	Orphanet:1377	Cataract-microcornea syndrome
CRYBA4	Orphanet:441452	Early-onset lamellar cataract
CRYGB	Orphanet:441452	Early-onset lamellar cataract
CRYGB	Orphanet:98988	Early-onset anterior polar cataract
CRYGB	Orphanet:98994	Total early-onset cataract
CRYGC	Orphanet:1377	Cataract-microcornea syndrome
CRYGC	Orphanet:441452	Early-onset lamellar cataract
CRYGC	Orphanet:98984	Pulverulent cataract
CRYGC	Orphanet:98991	Early-onset nuclear cataract
CRYGD	Orphanet:1377	Cataract-microcornea syndrome
CRYGD	Orphanet:441452	Early-onset lamellar cataract
CRYGD	Orphanet:98984	Pulverulent cataract
CRYGD	Orphanet:98989	Cerulean cataract
CRYGD	Orphanet:98990	Coralliform cataract
CRYGD	Orphanet:98991	Early-onset nuclear cataract
CRYGS	Orphanet:441452	Early-onset lamellar cataract
CRYGS	Orphanet:98985	Early-onset sutural cataract
HSF4	Orphanet:441452	Early-onset lamellar cataract
HSF4	Orphanet:98994	Total early-onset cataract
MIP	Orphanet:441452	Early-onset lamellar cataract
MIP	Orphanet:98985	Early-onset sutural cataract
MIP	Orphanet:98989	Cerulean cataract
MIP	Orphanet:98991	Early-onset nuclear cataract
MIP	Orphanet:98993	Early-onset posterior polar cataract
MIP	Orphanet:98994	Total early-onset cataract

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BFSP2	HGNC:1041	ENSG00000170819	Q13515	Phakinin	gencc
CRYAA	HGNC:2388	ENSG00000160202	P02489	Alpha-crystallin A chain	gencc
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	gencc
CRYBA1	HGNC:2394	ENSG00000108255	P05813	Beta-crystallin A3	gencc
CRYBA4	HGNC:2396	ENSG00000196431	P53673	Beta-crystallin A4	gencc
CRYGB	HGNC:2409	ENSG00000182187	P07316	Gamma-crystallin B	gencc
CRYGC	HGNC:2410	ENSG00000163254	P07315	Gamma-crystallin C	gencc
CRYGD	HGNC:2411	ENSG00000118231	P07320	Gamma-crystallin D	gencc
CRYGS	HGNC:2417	ENSG00000213139	P22914	Gamma-crystallin S	gencc
HSF4	HGNC:5227	ENSG00000102878	Q9ULV5	Heat shock factor protein 4	gencc
TNPO1	HGNC:6401	ENSG00000083312	Q92973	Transportin-1	gencc
MIP	HGNC:7103	ENSG00000135517	P30301	Lens fiber major intrinsic protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BFSP2	Phakinin	Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.
CRYAA	Alpha-crystallin A chain	Contributes to the transparency and refractive index of the lens.
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.
CRYBA1	Beta-crystallin A3	Crystallins are the dominant structural components of the vertebrate eye lens.
CRYBA4	Beta-crystallin A4	Crystallins are the dominant structural components of the vertebrate eye lens.
CRYGB	Gamma-crystallin B	Crystallins are the dominant structural components of the vertebrate eye lens.
CRYGC	Gamma-crystallin C	Crystallins are the dominant structural components of the vertebrate eye lens.
CRYGD	Gamma-crystallin D	Crystallins are the dominant structural components of the vertebrate eye lens.
CRYGS	Gamma-crystallin S	Crystallins are the dominant structural components of the vertebrate eye lens.
HSF4	Heat shock factor protein 4	Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE).
TNPO1	Transportin-1	Functions in nuclear protein import as nuclear transport receptor.
MIP	Lens fiber major intrinsic protein	Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 12 · 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	12	1.8×	9e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BFSP2	Other/Unknown	no		Keratin_I, IF_rod_dom
CRYAA	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
CRYBA1	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
CRYBA4	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
CRYGB	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
CRYGC	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
CRYGD	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
CRYGS	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
HSF4	Other/Unknown	no		HSF_DNA-bd, WH-like_DNA-bd_sf, WH_DNA-bd_sf
TNPO1	Other/Unknown	no		Importin-beta_N, ARM-like, ARM-type_fold
MIP	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like

Expression context

Cohort genes with no expression data: 0.

6 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)	1
broad (>20)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
primordial germ cell in gonad	6
lens of camera-type eye	3
right lobe of liver	2
cerebellar cortex	2
cerebellar hemisphere	2
adult mammalian kidney	1
liver	1
cardiac ventricle	1
left ventricle myocardium	1
middle frontal gyrus	1
frontal pole	1
skeletal muscle tissue of rectus abdominis	1
sperm	1
testis	1
ventricular zone	1
right hemisphere of cerebellum	1
caput epididymis	1
cauda epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BFSP2	111	tissue_specific	yes	lens of camera-type eye, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
CRYAA	42		marker	adult mammalian kidney, right lobe of liver, liver
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle
CRYBA1	138	tissue_specific	yes	lens of camera-type eye, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
CRYBA4	72	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, frontal pole
CRYGB	35	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, sperm, skeletal muscle tissue of rectus abdominis
CRYGC	15	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis
CRYGD	60	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, ventricular zone
CRYGS	179	tissue_specific	yes	lens of camera-type eye, cerebellar hemisphere, cerebellar cortex
HSF4	186	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TNPO1	295	ubiquitous	marker	corpus epididymis, caput epididymis, cauda epididymis
MIP	91	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 33.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYAB	3,368
TNPO1	3,147
MIP	2,496
CRYGC	2,111
CRYAA	1,464
BFSP2	1,203
HSF4	967
CRYBA1	925
CRYBA4	601
CRYGS	513

Intra-cohort edges

A	B	Sources
BFSP2	CRYAA	string_interaction
BFSP2	CRYBA1	string_interaction
BFSP2	CRYBA4	string_interaction
BFSP2	CRYGB	string_interaction
BFSP2	CRYGC	string_interaction
BFSP2	CRYGD	string_interaction
BFSP2	CRYGS	string_interaction
BFSP2	HSF4	string_interaction
BFSP2	MIP	string_interaction
CRYAA	CRYAB	biogrid_interaction, intact
CRYAA	CRYBA1	biogrid_interaction, string_interaction
CRYAA	CRYBA4	string_interaction
CRYAA	CRYGB	string_interaction
CRYAA	CRYGC	biogrid_interaction, intact, string_interaction
CRYAA	CRYGD	biogrid_interaction, string_interaction
CRYAA	CRYGS	string_interaction
CRYAA	HSF4	string_interaction
CRYAB	CRYBA1	string_interaction
CRYAB	CRYBA4	string_interaction
CRYAB	CRYGB	string_interaction
CRYAB	CRYGC	biogrid_interaction, intact
CRYAB	CRYGD	biogrid_interaction, string_interaction
CRYAB	CRYGS	biogrid_interaction, intact, string_interaction
CRYBA1	HSF4	string_interaction
CRYBA4	HSF4	string_interaction
CRYBA4	MIP	string_interaction
CRYGB	CRYGC	biogrid_interaction, intact
CRYGC	CRYGD	biogrid_interaction
CRYGD	HSF4	string_interaction
CRYGD	MIP	string_interaction
CRYGS	HSF4	string_interaction
CRYGS	MIP	string_interaction
HSF4	MIP	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYAB	P02511	21
TNPO1	Q92973	21
CRYGD	P07320	16
CRYGS	P22914	12
CRYAA	P02489	5
CRYGB	P07316	2
HSF4	Q9ULV5	2
CRYBA4	P53673	1
CRYGC	P07315	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MIP	P30301	91.08
CRYBA1	P05813	88.27
BFSP2	Q13515	78.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 12 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HSF1-dependent transactivation	2	158.6×	6e-04	CRYAB, CRYBA4
Passive transport by Aquaporins	1	219.6×	0.015	MIP
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	158.6×	0.015	TNPO1
Attenuation phase	1	102.0×	0.015	CRYBA4
Postmitotic nuclear pore complex (NPC) reformation	1	102.0×	0.015	TNPO1
HSF1 activation	1	95.2×	0.015	CRYBA4
Aquaporin-mediated transport	1	92.1×	0.015	MIP
Intraflagellar transport	1	50.1×	0.025	TNPO1
Regulation of HSF1-mediated heat shock response	1	34.8×	0.032	CRYBA4
Transport of small molecules	1	6.3×	0.150	MIP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lens development in camera-type eye	9	280.9×	3e-20	CRYAA, CRYAB, CRYBA1, CRYBA4, CRYGB, CRYGC, CRYGD, CRYGS (+1 more)
visual perception	9	59.6×	4e-14	BFSP2, CRYAA, CRYBA1, CRYBA4, CRYGB, CRYGC, CRYGD, CRYGS (+1 more)
negative regulation of intracellular transport	2	936.2×	3e-05	CRYAA, CRYAB
apoptotic process involved in morphogenesis	2	468.1×	9e-05	CRYAA, CRYAB
lens fiber cell morphogenesis	2	351.1×	1e-04	CRYAA, CRYGB
tubulin complex assembly	2	280.9×	2e-04	CRYAA, CRYAB
lens fiber cell differentiation	2	175.5×	4e-04	CRYGD, HSF4
protein refolding	2	104.0×	0.001	CRYAA, CRYAB
response to hydrogen peroxide	2	78.0×	0.002	CRYAA, CRYAB
response to heat	2	70.2×	0.002	CRYAA, CRYAB
microtubule polymerization or depolymerization	1	1404.3×	0.003	CRYAB
response to UV-A	1	351.1×	0.013	CRYAA
regulation of programmed cell death	1	234.1×	0.016	CRYAB
gap junction-mediated intercellular transport	1	234.1×	0.016	MIP
maintenance of lens transparency	1	175.5×	0.019	MIP
lens fiber cell development	1	175.5×	0.019	BFSP2
positive regulation of anoikis	1	156.0×	0.020	CRYBA1
response to hypoxia	2	16.0×	0.020	CRYAA, CRYAB
homotypic cell-cell adhesion	1	140.4×	0.020	MIP
glutathione biosynthetic process	1	127.7×	0.021	CRYAA
negative regulation of amyloid fibril formation	1	108.0×	0.024	CRYAB
embryonic camera-type eye morphogenesis	1	93.6×	0.026	CRYAA
water transport	1	82.6×	0.026	MIP
microtubule-based process	1	82.6×	0.026	CRYAA
negative regulation of reactive oxygen species metabolic process	1	78.0×	0.026	CRYAB
negative regulation of gene expression	2	11.5×	0.026	CRYAA, CRYAB
protein stabilization	2	11.2×	0.027	CRYAA, CRYAB
stress-activated MAPK cascade	1	58.5×	0.033	CRYAB
cellular response to gamma radiation	1	50.1×	0.037	CRYAB
negative regulation of TOR signaling	1	46.8×	0.038	CRYBA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 12

Druggability breadth: 6 of 12 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
BFSP2	0	0
CRYAA	0	0
CRYAB	0	0
CRYBA1	0	0
CRYBA4	0	0
CRYGB	0	0
CRYGC	0	0
CRYGD	0	0
CRYGS	0	0
HSF4	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
CRYAA	25	Binding:25
CRYAB	13	Binding:13
CRYGC	9	Binding:9
CRYGD	9	Binding:9
TNPO1	7	Binding:7
HSF4	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; 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	12	BFSP2, CRYAA, CRYAB, CRYBA1, CRYBA4, CRYGB, CRYGC, CRYGD, CRYGS, HSF4 (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BFSP2	0	—
CRYAA	25	—
CRYAB	13	—
CRYBA1	0	—
CRYBA4	0	—
CRYGB	0	—
CRYGC	9	—
CRYGD	9	—
CRYGS	0	—
HSF4	1	—
TNPO1	7	—
MIP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.