Cataract 5, multiple types — comprehensive disease-characteristics report

Disease: Cataract 5, multiple types
Preferred symbol: CTRCT5
MONDO: MONDO:0007290
OMIM phenotype: 116800
Causal gene: HSF4
Inheritance: Autosomal dominant
Evidence scope: Human pedigrees and sporadic patients, supplemented by mouse, zebrafish, canine, cell-culture, transcriptomic, and proteomic experiments.

Important nomenclature boundary: CTRCT5 is the autosomal-dominant, usually isolated cataract phenotype caused principally by heterozygous HSF4 variants in its DNA-binding domain. It should not be conflated with Cataract 12, multiple types (OMIM 611597) caused by BFSP2, or automatically merged with recessive HSF4-related cataract.

1. Disease information

1.1 Definition and overview

Cataract 5, multiple types is a rare Mendelian lens disorder characterized by congenital, infantile, or early-childhood lens opacities with markedly variable morphology. Documented forms include lamellar, zonular, nuclear, pulverulent, anterior-polar, stellate, perinuclear, total, and “Marner-type” cataracts. The disorder is usually bilateral and progressive, although unilateral or very mild disease has been reported. It is caused by heterozygous germline variants in HSF4, encoding heat-shock transcription factor 4, on chromosome 16q22.1. [361][363]

The landmark gene-discovery study reported:

“We screened individuals of three Chinese families for mutations in HSF4 … and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder.”
— Bu et al., Nature Genetics, published June 24, 2002; PMID: 12089525 (PubMed). [48]

1.2 Identifiers and synonyms

OMIM designates the phenotype autosomal dominant and maps it to HSF4 at 16q22.1. MeSH classifies cataracts according to morphology or etiology under D002386. [271][361]

1.3 Data provenance

The knowledge base is aggregated disease-level information, not a single EHR-derived phenotype. Its principal sources are:

• Historical multigeneration pedigrees, including 132 affected individuals over eight generations in the original Marner family.
• Molecularly characterized Chinese and Danish families.
• Sporadic patients, including at least one de novo case.
• ClinVar laboratory submissions and aggregated diagnostic cohorts.
• Experimental mouse, zebrafish, and lens-cell models.

The large Danish family had mainly zonular cataract, with nuclear, anterior-polar, or stellate forms in some relatives; the Chinese linkage family had lamellar opacity surrounding a clear embryonic nucleus, with earliest recognized onset at 15 months. [96]

2. Etiology

2.1 Primary causal factor

The established cause of CTRCT5 is a heterozygous germline pathogenic or likely pathogenic variant in HSF4. Dominant variants are concentrated in the highly conserved N-terminal α-helical DNA-binding domain and are predominantly missense substitutions. The clustering and functional studies support impaired DNA binding and, for at least some variants, a dominant-negative mechanism rather than simple haploinsufficiency. [121][124][418]

HSF4 is a constitutively trimerized heat-shock transcription factor that controls lens-specific transcription, epithelial-cell proliferation, fiber-cell differentiation, proteostasis, autophagy, lysosomal function, and organelle removal. Cataract-causing variants can impair heat-shock-element recognition, protein–DNA contacts, protein folding, or oligomerization. [71]

2.2 Risk factors

2.3 Protective factors

No penetrance-reducing human HSF4 allele or validated genetic modifier has been established. Similarly, no diet, supplement, drug, or lifestyle intervention has been shown to prevent HSF4-mediated cataract.

Reasonable general eye-health measures—avoiding smoking, unnecessary ocular radiation, trauma, and excessive UV exposure, and controlling diabetes—may reduce superimposed acquired lens injury but should not be represented as primary prevention of this Mendelian disorder.

2.4 Gene–environment interaction

Direct human gene–environment evidence for CTRCT5 is limited. Experimentally, Hsf4 deficiency increases UVB-induced senescence in mouse lens epithelial cells, with increased p21^Cip1^ and senescence-associated cytokines. HSF4 normally binds the Cdkn1a/p21 promoter and recruits EZH2, increasing repressive H3K27me3. This supplies a plausible interaction between impaired HSF4 function and environmental oxidative/UV stress, but it is not yet a quantified clinical interaction in CTRCT5 families (PMID: 34339841). [413]

Functional testing also found that five congenital-cataract HSF4 substitutions inhibited DNA binding, whereas weaker age-related-cataract substitutions had little effect, leading the investigators to suggest that other genetic and environmental factors may be necessary for the latter variants (PMID: 20670914). [418]

3. Phenotypes

Frequencies for individual morphologies cannot be estimated reliably because published families are small, ascertainment differs, and morphology may change with age.

The recognized disease-level HPO set explicitly includes nuclear, zonular, pulverulent, anterior-polar, and lamellar cataracts. Clinical descriptions additionally support progressive, bilateral early-childhood opacities with substantial intrafamilial variation. [362][363]

In a broader treated-childhood-cataract cohort, median functional visual ability indicated moderate impairment, and mean vision-related quality-of-life score was 65.67 where 96 represented normal. These values are not CTRCT5-specific but describe the likely burden of clinically significant pediatric cataract. [140]

4. Genetic and molecular information

4.1 Gene annotation

4.2 Principal dominant variants

Transcript numbering differs between publications. For example, historical p.Ala20Asp/p.Leu115Pro/p.Arg120Cys can appear as p.Ala19Asp/p.Leu114Pro/p.Arg119Cys on newer transcripts.

The five variants found in a 42-family southeast-Chinese cohort accounted for 11.9% of that selected cohort; this is not a population prevalence. Four missense variants were classified as likely pathogenic and c.233-1G>A as pathogenic, but their direct functional evidence was largely computational rather than biochemical. [95]

4.3 Molecular consequences

Five congenital-cataract-associated missense variants inhibited HSF4 DNA binding in vitro, linking the variants to reduced expression of lens proteins. Structural modeling suggests four nonexclusive mechanisms:

1. Loss of heat-shock-element recognition.
2. Perturbation of direct protein–DNA contacts.
3. Destabilization or misfolding of the DNA-binding domain.
4. Impaired HSF4 oligomerization. [71][418]

Dominant-negative action is plausible because HSF4 is constitutively trimeric: incorporation of a DBD-mutant subunit may poison DNA binding by the complex. This is mechanistically stronger for DBD missense variants than for whole-gene deletions.

4.4 Modifier genes and epigenetics

No validated human modifier gene predicts CTRCT5 severity. Experimental pathway partners include:

• CRYAB, CRYGS, BFSP1, BFSP2: lens structural/proteostasis targets.
• DNASE2B: fiber-cell denucleation.
• ATG9A: autophagosome formation.
• TP53, CDKN1A, FAS, BAX: cell-cycle and differentiation network.
• EZH2: HSF4-recruited histone methyltransferase.
• PAX6, BRG1/SMARCA4 and SNF2H/SMARCA5: broader lens differentiation and chromatin context.

HSF4 can recruit EZH2 to increase H3K27me3 at the CDKN1A/p21 promoter in experimental lens cells. This is an epigenetic mechanism of HSF4 action, but no CTRCT5-specific diagnostic methylation signature is established. [413]

4.5 Chromosomal abnormalities

No recurrent CTRCT5-defining translocation, inversion, or aneuploidy is known. Rare deletions encompassing HSF4 have been submitted as pathogenic, so deletion/duplication analysis is appropriate when sequence testing is negative, especially if additional congenital abnormalities suggest a contiguous-gene disorder. [93]

5. Environmental information

CTRCT5 is primarily genetic. There is no infectious agent, toxin, or nutritional deficiency necessary for disease.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

1. A heterozygous germline HSF4 DNA-binding-domain variant leads to altered HSF4 folding, heat-shock-element recognition, protein–DNA interaction, or oligomer function.
2. Defective HSF4 transcriptional activity leads to reduced expression of lens crystallins and cytoskeletal genes, including CRYGS, CRYAB, BFSP1, and BFSP2.
3. Reduced crystallin/chaperone and beaded-filament expression leads to impaired protein stability, abnormal fiber-cell architecture, and protein/inclusion accumulation.
4. Deficient HSF4 regulation of TP53, FAS, BAX, and growth-factor networks leads to abnormal epithelial proliferation and mistimed fiber-cell differentiation.
5. Reduced DNASE2B transcription leads to incomplete degradation of lens-fiber nuclei.
6. Reduced ATG9A transcription leads to defective autophagosome biogenesis and maturation.
7. Autophagic and lysosomal defects lead to persistence of nuclei, mitochondria, endoplasmic reticulum, and Golgi in differentiating lens fibers.
8. Persistent organelles and disordered fiber cells lead to light scattering and loss of lens transparency.
9. Lens opacity leads to lamellar, nuclear, zonular, stellate, anterior-polar, perinuclear, or total cataract.
10. Central dense opacity during visual development leads to deprivation amblyopia, nystagmus, strabismus, and permanent visual impairment if treatment is delayed.

Steps 2–7 are strongly demonstrated in knockout/mutant animals and cultured lens cells but remain partly inferred for each individual human dominant variant.

6.2 Lens structural-gene branch

In Hsf4-null mice, Crygs, Bfsp1, and Bfsp2 are markedly downregulated; Bfsp1 and Bfsp2 mRNA fell more than sevenfold at eight weeks. The mice develop progressive postnatal opacity, swollen/disorganized fibers, and altered αA-crystallin post-translational modification (PMID corresponding to the 2009 study). [186][265]

Suggested ontology annotations:

• GO:0002088 lens development in camera-type eye
• GO:0070306 lens fiber-cell differentiation
• GO:0070307 lens fiber-cell development
• GO:0070309 lens fiber-cell morphogenesis
• GO:0005212 structural constituent of eye lens

6.3 Cell-cycle and differentiation branch

HSF4 stabilizes nuclear p53, activates p21, and imposes G1/S arrest in cultured human lens epithelial cells. Cataract-causing mutants did not stabilize p53 normally (PMID: 25940838). [200]

In hsf4-null zebrafish, lens epithelial cells overproliferate, fiber cells become overabundant and disorganized, activated caspase-3 and p53 decline, and terminal organelle elimination fails. Partial rescue by tp53, fas, or bax mRNA supports a causal HSF4→p53/FAS/BAX differentiation axis (PMID: 28981088). [202][256]

Suggested terms:

• GO:0007049 cell cycle
• GO:0000082 G1/S transition
• GO:0043065 positive regulation of apoptotic process
• CL:0002224 lens epithelial cell
• CL:0011004 lens fiber cell

6.4 Denucleation branch

HSF4 binds the DNASE2B promoter and promotes DNase IIβ expression and activity. HSF4 knockdown in zebrafish caused reduced DNase activity and incomplete lens-fiber denucleation (PMID: 23507146). [182]

Suggested terms:

• GO:0044804 autophagy of nucleus
• GO:1903008 organelle disassembly
• GO:0070306 lens fiber-cell differentiation

6.5 Autophagy branch — principal 2023 development

A 2023 mouse and cell study found that HSF4 directly activates ATG9A. In HSF4^del42^ lenses, 417 genes were downregulated and 82 upregulated at both postnatal day 3 and day 7; ATG9A protein was markedly reduced. Autophagosome initiation, maturation, lysosome colocalization, and clearance of mitochondria, ER and Golgi were impaired. ChIP localized HSF4 binding to heat-shock elements in the Atg9a promoter (PMID: 37266953, published June 1, 2023). [218]

“Our findings demonstrate that HSF4 facilitates organelle degradation probably by transcriptionally activating autophagy during lens terminal differentiation.” [355]

Relevant terms:

• GO:0006914 autophagy
• GO:0016236 macroautophagy
• GO:0097352 autophagosome maturation
• GO:0005776 autophagosome
• GO:0005739 mitochondrion
• GO:0005783 endoplasmic reticulum
• GO:0005794 Golgi apparatus
• GO:0005634 nucleus

6.6 Lysosome/mTOR branch

HSF4 regulates CRYAB. Experimental evidence suggests αB-crystallin stabilizes an ATP6V1A–mTORC1 complex needed for lysosomal acidification. In hsf4-null zebrafish, reduced cryaba and increased lysosomal pH are proposed to impair organelle degradation. [187]

6.7 Immune and metabolic involvement

CTRCT5 is not primarily inflammatory, autoimmune, or metabolic. Secondary oxidative stress and senescence-associated cytokines are plausible downstream phenomena. No reproducible blood, aqueous-humor, or systemic metabolomic signature exists.

6.8 Molecular profiling and advanced technology

7. Anatomical structures affected

The lens contains a proliferating epithelium and a bulk mass of terminally differentiated fiber cells; both are affected experimentally, with terminal fiber-cell organelle clearance being particularly important. [386]

Disease is usually bilateral but may be asymmetric or, rarely, unilateral. There is no established systemic-organ involvement in classic human CTRCT5.

8. Temporal development

8.1 Onset and course

• Typical onset: congenital, infantile, or early childhood.
• Earliest documented in the original Chinese family: 15 months, although other molecularly confirmed families had cataract at birth.
• Pattern: insidious developmental opacity rather than acute inflammation.
• Course: stable in some small opacities but commonly progressive.
• Duration: lifelong unless the lens is surgically removed.
• Stage concept: small/non-visually significant opacity → enlarging or denser central opacity → visually significant cataract → amblyopia/strabismus/nystagmus → postoperative aphakia or pseudophakia with lifelong surveillance.

8.2 Critical period

The critical window is early visual development. Visually significant unilateral cataract is generally removed at approximately 4–6 weeks, and bilateral cataracts by 6–8 weeks, balancing amblyopia prevention against anesthesia and glaucoma risk. [151][153]

The historical suggestion of genetic “anticipation” in the Marner pedigree is not supported by a repeat-expansion mechanism and may reflect ascertainment or age-dependent recognition. It should not be encoded as proven anticipation.

9. Inheritance and population

9.1 Inheritance characteristics

9.2 Epidemiology

No CTRCT5-specific prevalence or incidence estimate is available. It is considerably rarer than congenital cataract as a group.

For context, pooled congenital-cataract prevalence is about 4.24 per 10,000 persons, with substantial geographic heterogeneity; childhood cataract prevalence ranges from 0.32–22.9 per 10,000 and incidence from 1.8–3.6 per 10,000 children per year. These are not HSF4-specific figures. [136][137]

In one selected Chinese familial congenital-cataract cohort, HSF4 variants were found in 5/42 families (11.9%), but referral and candidate-gene selection prevent generalization. [95]

10. Diagnostics

10.1 Clinical evaluation

AAP/AAO/AAPOS recommendations support red-reflex examination from the newborn period, with referral for an abnormal reflex. [287][289]

10.2 Laboratory investigations

For an otherwise healthy child with a clear dominant family history and a pathogenic HSF4 variant, broad metabolic and infectious testing has low expected yield. If bilateral cataract is unexplained or accompanied by systemic signs, selectively consider:

• Urine reducing substances.
• Erythrocyte galactose-1-phosphate uridyltransferase and galactokinase.
• Serum glucose, calcium, phosphate, renal and liver tests.
• Infection testing for rubella, CMV, toxoplasmosis, herpes/varicella and syphilis, guided by maternal/neonatal history.
• Additional metabolic studies based on phenotype.

A 2023 retrospective study found that although 68% of tested children had positive TORCH IgG, no infection was confirmed; initial galactosemia or urine-reducing-substance abnormalities were likewise not confirmed. The authors concluded that genetic testing should be strongly considered and infection/metabolic tests should be clinically targeted (PMID: 37717619). [307]

10.3 Genetic testing strategy

1. Multigene congenital/childhood cataract panel including HSF4, crystallins, connexins, transcription factors, membrane proteins, and syndromic cataract genes.
2. Ensure deletion/duplication analysis and adequate coverage of HSF4 coding exons and splice junctions.
3. If a known familial HSF4 variant exists, use targeted testing for relatives, prenatal diagnosis, or preimplantation testing.
4. If panel-negative, use trio WES or WGS, particularly with atypical ocular/systemic findings.
5. Reanalyze negative or VUS results periodically.
6. Confirm pathogenic variants and segregation by an orthogonal method where clinically required.

In a diverse US pediatric cohort published February 28, 2023, diagnostic yields were 46.2% for WES, 37.5% for targeted cataract panels, and 11% for microarray; 16% of reviewed variants had discrepant reclassifications, emphasizing periodic reassessment (PMID: 36980880). [166][174]

CMA, karyotyping, and FISH are not first-line tests for isolated familial CTRCT5 but may be appropriate with developmental delay, dysmorphism, multiple congenital anomalies, or a suspected genomic deletion. Mitochondrial and repeat-expansion tests are not routine.

10.4 Variant interpretation

• Use current ACMG/AMP criteria.
• Confirm transcript and residue numbering.
• Strong evidence includes DBD location, absence/rarity in gnomAD, segregation, de novo status, functional impairment of DNA binding, and consistent cataract morphology.
• Do not diagnose CTRCT5 from a VUS alone.
• Recessive variants outside the DBD require biallelic interpretation and may represent a different HSF4-related disease entity.

10.5 Differential diagnosis

11. Outcome and prognosis

11.1 Survival and mortality

Classic isolated CTRCT5 is not expected to reduce life expectancy and has no known disease-specific mortality. Five- and ten-year survival statistics are therefore not applicable.

11.2 Visual prognosis

Prognosis depends mainly on:

• Opacity density, size and location.
• Unilateral versus bilateral disease.
• Age at recognition and surgery.
• Duration of visual deprivation.
• Quality and adherence to optical correction and patching.
• Associated nystagmus or strabismus.
• Postoperative glaucoma, visual-axis opacity, refractive error and retinal complications.

Anatomical removal of the cataract does not reverse established amblyopia. In the Infant Aphakia Treatment Study of unilateral congenital cataract, only about 25% achieved 20/40 or better and 44% had 20/200 or worse vision at age 10.5 years, despite specialist treatment; this is not HSF4-specific but illustrates the importance of early visual development. [341][344]

11.3 Complications

• Deprivation or anisometropic amblyopia.
• Strabismus and loss of stereopsis.
• Nystagmus in severe early bilateral disease.
• Glare, reduced contrast sensitivity and educational limitations.
• Surgical inflammation and visual-axis opacification.
• Aphakic or pseudophakic refractive error and progressive myopic shift.
• Secondary glaucoma requiring lifelong surveillance.
• Rare retinal detachment.

At ten years after unilateral infant cataract surgery, IATS estimated a 22% cumulative glaucoma probability and 40% probability of glaucoma or glaucoma-suspect status; rates were similar after primary IOL and aphakic/contact-lens management. [343]

12. Treatment

12.1 Current treatment algorithm

A central opacity larger than approximately 3 mm, obscured fundus reflex, poor fixation, strabismus, or nystagmus generally indicates visual significance. [151]

12.2 Surgical details

Typical pediatric surgery may include:

• Lens aspiration/lensectomy.
• Anterior capsulotomy.
• Primary posterior capsulotomy and anterior vitrectomy in young children to reduce visual-axis opacification.
• Aphakic correction or age-dependent IOL implantation.
• Immediate and sustained amblyopia treatment.

In the randomized IATS, primary IOL implantation did not produce better visual acuity at age 10.5 years than aphakia corrected initially with contact lenses. The IOL group underwent more additional intraocular procedures—71 versus 38 by ten years. [336][341]

12.3 Pharmacotherapy

No medication reverses or reliably prevents established CTRCT5. Pharmacotherapy is supportive and perioperative rather than genotype-specific:

• Topical corticosteroids for postoperative inflammation.
• Cycloplegics/mydriatics postoperatively as indicated.
• Glaucoma-lowering medication when needed.
• Atropine penalization in selected amblyopia cases.

No established CPIC or PharmGKB genotype-guided prescribing recommendation exists for HSF4.

12.4 Experimental therapy

The major recent experimental lead is autophagy enhancement. In HSF4^del42^ mice, rapamycin—an mTOR inhibitor, CHEBI:9168—increased LC3-II, reduced p62, and improved removal of retained mitochondria, ER and Golgi. The study used 10 μM ex vivo and 7.5 mg/kg intraperitoneally in neonatal mice. It did not demonstrate restoration of human vision or establish pediatric safety. [348]

Therefore:

• Rapamycin is not recommended clinically for CTRCT5.
• No approved HSF4 gene replacement, CRISPR, ASO, siRNA, mRNA, stem-cell or lens-regeneration treatment exists.
• No genotype-specific human clinical trial with an established NCT identifier was identified.
• Gene editing faces the additional challenge that dominant DBD variants may require allele-specific correction or silencing rather than simple gene supplementation.

13. Prevention

13.1 Primary prevention

The mutation cannot presently be prevented after conception. Reproductive options after identifying the familial variant include:

• Genetic counseling.
• Partner/family testing as appropriate.
• Prenatal diagnosis by chorionic-villus sampling or amniocentesis.
• IVF with preimplantation genetic testing for monogenic disease.
• Use of donor gametes or adoption.

Prenatal genotype predicts risk but not reliably cataract morphology or severity because expressivity is variable.

13.2 Secondary prevention

• Red-reflex examination in newborns and at subsequent well-child visits.
• Early ophthalmic assessment of infants with an affected parent.
• Cascade testing for the familial variant.
• Serial slit-lamp examinations in mildly affected or genotype-positive children.
• Prompt treatment before irreversible amblyopia.

13.3 Tertiary prevention

• Rapid postoperative optical correction.
• Sustained amblyopia therapy and adherence support.
• Lifelong IOP/glaucoma surveillance.
• Management of refractive change and visual-axis opacification.
• Low-vision, educational and psychosocial support when needed.

There is no relevant immunization or antimicrobial prophylaxis for genetic CTRCT5. Rubella vaccination prevents rubella-associated congenital cataract generally but does not prevent HSF4-mediated disease.

14. Other species and natural disease

Canine HSF4 cataract illustrates how different lesions at the same locus produce recessive or semidominant disease and variable morphology. HSF4-associated cataracts have been reported in Australian/Miniature/Toy Shepherds, Boston Terriers, Staffordshire Bull Terriers, French Bulldogs, and Miniature Pinschers. [228][229]

There is no zoonotic potential and no cross-species transmission; these are independent inherited disorders.

15. Model organisms

The 2004 knockout study summarized its central observation as:

“HSF4-null mice had cataract with abnormal lens fiber cells containing inclusion-like structures, probably due to decreased expression of γ-crystallin.” [197]

The 2009 investigators concluded that knockout mice only partially mimic human HSF4 cataract, an important limitation because the human dominant disorder usually involves a heterozygous DBD missense allele rather than biallelic absence of protein. [265]

Overall evidence assessment

• Gene–disease validity: Strong/definitive for HSF4 and autosomal-dominant CTRCT5, supported by linkage, segregation, de novo occurrence, variant clustering, functional assays, and multiple animal models. GenCC assessments identify a strong-to-definitive relationship. [29]
• Core phenotype: Isolated, usually bilateral, congenital or early-childhood cataract with variable morphology and frequent progression.
• Best-supported human mechanism: Dominant DBD variants impair HSF4 DNA-binding/transcriptional function.
• Best-supported downstream biology: Abnormal crystallin and beaded-filament expression, epithelial proliferation/fiber differentiation, p53 signaling, DNASE2B-mediated denucleation, lysosomal function, and ATG9A-dependent autophagy.
• Major 2023–2024 development: Identification of the HSF4→ATG9A autophagy axis and partial rescue of organelle-clearance defects with rapamycin in mice, complemented by a 2024 synthesis of HSF4 transgenic cataract models. This remains preclinical. [348][184]
• Current standard of care: Early detection, timely cataract extraction when visually significant, immediate optical correction, intensive amblyopia management, and lifelong glaucoma/refractive surveillance.
• Principal knowledge gaps: CTRCT5-specific prevalence, formal penetrance estimates, longitudinal natural history by genotype, human modifier genes, patient-derived single-cell/spatial data, and a safe molecular treatment that preserves or restores the native lens.

Reference Validation

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Term Validation

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Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• DOID:0110255 (2 mentions) - the report calls it "Disease Ontology"; DOID calls it cataract 5 multiple types
• NCBITaxon:9615 (4 mentions) - the report calls it "Dog, Staffordshire Bull Terrier", "Dog, French Bulldog and Miniature Pinscher", "Dog, Australian Shepherd and related Miniature/Toy Shepherds"; NCBITaxon calls it Canis lupus familiaris

Obsolete terms

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• HP:0010700 (obsolete Total cataract) (1 mention) - replaced by HP:0000518

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• NCBITaxon:9615 - called "Dog, Staffordshire Bull Terrier", "Dog, French Bulldog and Miniature Pinscher", "Dog, Australian Shepherd and related Miniature/Toy Shepherds"

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