Autosomal dominant, autosomal recessive, X-linked
Cataracts are a clouding of the lens in the eye, defined as opacification of the normally transparent crystalline lens. Cataracts are very common in older people and mostly related to aging. Cataracts can occur in one or both eyes affecting vision, i.e. clouding in the lens results in blurred vision. Unilateral cataracts are usually isolated and sporadic whereas bilateral cataracts are often inherited and associated with other diseases.
Cataracts can be defined by the age at onset as:
- Congenital or infantile cataract that presents within the first years of life
- Juvenile cataract that presents within the first decade of life
- Presenile cataract that presents before the age of 45 years
- Senile or age-related cataract that presents after 45 years of age.
Congenital cataract (CC) is one of the most treatable forms of visual impairment and blindness during infancy. The prevalence of cataracts in children has been estimated between 1-15:10,000 cases3 and estimated prevalence of congenital cataracts is 1-6 cases per 10,000 live births1.
There are three major types of cataracts, affecting different parts of the lens of the eye:
- Nuclear sclerotic cataracts, the most common type of cataract that forms in the center of the lens, resulting in gradual hardening and yellowing of the lens.
- Posterior subcapsular cataracts that develop rapidly as a small cloudy area on the back surface of the lens, beneath the lens capsule (“subcapsular”). Subcapsular cataracts result in reading problems and the appearance of "halo" effects around lights.
- Cortical cataracts develop in the lens cortex as a white opacity, which appear as small fissures that are causing scattering of the light and resulting in blurred vision.
Clinically, cataracts are important when they interfere with vision. In general, major signs and symptoms of cataracts include:
- Clouded, blurred or dim vision
- Increasing difficulty with vision at night
- Sensitivity to light and glare
- Need for brighter light for reading and other activities
- Seeing "halos" around lights
- Frequent changes in eyeglass or contact lens prescription
- Fading or yellowing of colors
- Double vision in a single eye
Approximately 50% of all congenital cataract cases may have a genetic cause. The most common causes of congenital cataracts are pathogenic variants in lens crystallins-associated genes (CRYAA, CRYAB, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD) which account for ~50% of all cases1, 2, 4. Further common causes of CC (15%) are pathogenic variants in genes encoding connexins (GJA3, GJA8) 4. An additional 10% of hereditary cataracts have pathogenic variants in genes encoding transcription factors, and 10% in intermediate filaments (5%) or aquaporin (5%) 4.
Congenital cataracts can be isolated (70% of cases)3 or accompanied by other ophthalmological conditions, such as microphthalmia or aniridia. CC may also be a part of multisystem genetic disorders, such as Lowe oculocerebrorenal syndrome (OCRL), Nance–Horan syndrome (NHS), or neurofibromatosis type 2 (NF2).
There are currently more than 40 genetic loci to which isolated cataracts have been mapped with specific genes identified in majority of cases. CENTOGENE´s cataract panel includes 45 genes associated with different subtypes of cataract (Table 1).
Considering the growing number of genetic causes of cataract and the fact that the incidence of cataract continues to increase with the ageing of the population, medical treatment of cataracts is highly desired. Mostly it includes surgical treatment with phacoemulsification and intraocular lens implantation.
CENTOGENE´s cataract panel includes all genes shown to be associated with cataract to date and it can be used for simultaneous testing of dozens of cataract-associated genes, resulting in fast and precise molecular diagnostics of possibly underlying genetic forms of familial cataract in affected patients. Thus, CENTOGENE offers the cataract panel (genes: AGK, BCOR, BFSP1, BFSP2, CHMP4B, CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGB, CRYGC, CRYGD, CRYGS, CTDP1, EPHA2, EYA1, FOXC1, FOXE3, FTL, FYCO1, GALK1, GCNT2, GJA3, GJA8, HSF4, LEMD2, LIM2, LSS, MAF, MIP, NHS, P3H2, PAX6, PITX3, SIPA1L3, SLC16A12, TDRD7, UNC45B, VIM, VSX2, WFS1) including full gene sequencing, deletion/duplication analysis of selected genes (WFS1, PAX6, EYA1, FOXC1).
The differential diagnosis of cataract disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Corneal disease
- Optic nerve disease
- Eye injury, eye tumors
- Macular disease
- Medications affecting central nervous system
CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Cataract using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cataract panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no pathogenic variant is identified after analysis of the Cataract panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for this particular gene testing:
- Individuals with a family history of disease and presentation of the most common symptoms cataract and co-occurred conditions
- Individuals without a positive family history, but with symptoms resembling this disease
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.
Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.
Overview of genes underlying hereditary forms of cataract, included in CENTOGENE´s cataract NGS panel
|Protein||Inh.||% of pathogenic variants||Allelic disorders|
|Acylglycerol kinase||AR||Rare||Cataract 38 |
Cataract and cardiomyopathy
|Bcl6 corepressor||XLD||Rare for cataract |
>1% for MAC 5
|Microphthalmia syndromic 2 |
Microphtalmia and cataract
|Beaded filament protein 1||AR||Rare 6,7||Cataract 33 |
|Beaded filament protein 2||AD||12/384 Chinese population 6,7||Cataract 12 multiple types|
|Chromatin modifying protein 4B||AD||Rare8||Cataract 31 multiple types|
|Crystallin alpha 1||AD||Rare9||Cataract 9 multiple types |
Open angle glaucoma
|Crystallin alpha 2||AD, AR||Rare9||Cataract 16 multiple types |
Myofibrillar myopathy 2
Dilated cardiomyopathy 1II
|Crystallin beta 1||AD||Rare9||Cataract 10 multiple types|
|Crystallin beta 2||AD, AR||Rare9||Cataract 42|
|Crystallin beta 4||AD||Rare9||Cataract 23 multiple types |
Primary angle-closure glaucoma
|Crystallin beta B1||AD, AR||Rare9||Cataract 17 multiple types|
|Crystallin beta B2||AD||Rare9||Cataract 3 multiple types|
|Crystallin beta B3||AD, AR||Rare9||Cataract 22|
|Crystallin gamma-B||AD||Rare9||Cataract 39 multiple types|
|Crystallin gamma-C||AD||Rare9||Cataract 2 multiple types|
|Crystallin gamma-D||AD||Rare9||Cataract 4 multiple types|
|Crystallin gamma-S||AD||Rare9||Cataract 20 multiple types|
|Transcription factor CTD of POLR2A||AR||7% carrier rate for c.863+389C>T in Roma/Gypsy population 10, 11||Congenital cataracts, facial dysmorphism, and neuropathy|
|Ephrin receptor A2||AD||4.7% in Australia 12||Cataract 6 multiple types|
|eyes absent protein 1||AD||40% for BOR13||Anterior segment anomalies with or without cataract |
Branchiootorenal Spectrum Disorders (BOR)
Branchiootic syndrome 1
Branchiootorenal syndrome 1, with or without cataracts
|Transcription factor Forkhead box E3||AD||Rare||Anterior segment dysgenesis 3 |
Axenfeld-Rieger syndrome 3
|Transcription factor Forkhead box C2||AR||2.5% for MAC14||Anterior segment dysgenesis 2 |
Cataract 34 multiple types
|Ferritin light chain||AD, AR||80% for Neuroferritinopathy 15||Hyperferritinemia-cataract syndrome |
L-ferritin deficiency, dominant and recessive
Neurodegeneration with brain iron accumulation 3
|Transcription factor FYCO1||AR||Rare||Cataract 18|
|Galactokinese 1||AR||Rare||Galactokinase deficiency with cataracts|
|Glucosaminyl transferase 2||AD, AR||Rare||Cataract 13 with adult I phenotype |
Adult I phenotype without cataract
|GAP junction protein A3; Connexin 46||AD||Rare||Cataract 14 multiple type|
|GAP junction protein A8; Connexin 50||AD||Rare||Cataract 1 multiple type|
|Heat-shock transcription factor 4||AD||2/69 in Chinese population16||Cataract 5 multiple type|
|Nuclear transmembrane protein 25||AR||Rare||Cataract 46 juvenile-onset|
|Lens intristic membrane protein 2||AR||Rare||Cataract 19 multiple types|
|Lanosterol synthase||AR||Rare||Cataract 44|
|Transcription factor MAF||AD||Rare||Cataract 21 multiple types |
|Major lens intrinsic protein||AD||Rare||Cataract 15 multiple type|
|NHS actin remodeling regulator||XLD||Rare||Cataract 40, X-linked |
|Prolyl 3-hydrolase||AR||Rare||Myopia, high, with cataract and vitreoretinal degeneration|
|Transcriptional factor paired box 6||AD||94% (67/71) for Anyridia17 |
80% in Wilms tumor with aniridia 18
2% for MAC 5
|Cataract with late-onset corneal dystrophy, Coloboma of optic nerve, Coloboma, ocular, Aniridia Morning glory disc anomaly, Anterior segment dysgenesis 5, multiple subtypes |
Foveal hypoplasia 1
Optic nerve hypoplasia
|PAX6-regulated transcription factor 3||AD||Rare||Cataract 11 multiple types |
Anterior segment dysgenesis 1, multiple subtypes
|SIPA1-proliferation protein 3||AR||Rare||Cataract 45|
|Monocarboxylate transporter 12||AD||Rare||Cataract 47 with microcornea|
|Tudor domain regulating protein 7||AR||Rare||Cataract 36|
|Myosin-specific shaperone UNC45||AD||Rare||Cataract 43|
|Vimentin||AD||Rare||Cataract 30 pulverulent|
|Homeobox protein 10||AR||Rare||Microphthalmia with coloboma 3 |
|Wolframin||AD, AR||Rare||Cataract 41 |
Wolfram syndrome-like disease
Deafness, autosomal dominant 6/14/38
More information on CENTOGENE´s Cataract panel can be found in our genetic test catalogue.