1. NGS panel - Genetic testing for cataract

Cataract

March 27, 2017

Clinical features

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 mutations 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 mutations in genes encoding connexins (GJA3, GJA8) 4. An aqdditional 10% of hereditary cataracts have mutations 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).


Differential diagnosis

The differential diagnosis of cataract disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Corneal disease
  • Glaucoma
  • Optic nerve disease
  • Eye injury, eye tumors
  • Macular disease
  • Medications affecting central nervous system

Testing strategy

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 mutation 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.


Referral reasons

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).

Test utility

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 mutations, 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

Gene OMIM
chr. locus
Protein Inh. % of mutations Allelic disorders
AGK 610345
7q34
Acylglycerol kinase AR Rare Cataract 38
Cataract and cardiomyopathy
Sengers syndrome
BCOR 300485
Xp11.4
Bcl6 corepressor XLD Rare for cataract
>1% for MAC 5
Microphthalmia syndromic 2
Microphtalmia and cataract
Oculofaciocardiodental syndrome
BFSP1 603307
20p12.1
Beaded filament protein 1 AR Rare 6,7 Cataract 33
Juvenile cataract
BFSP2 603212
3q22.1
Beaded filament protein 2 AD 12/384 Chinese population 6,7 Cataract 12 multiple types
CHMP4B 610897
20q11.22
Chromatin modifying protein 4B AD Rare8 Cataract 31 multiple types
CRYAA 123580
21q22.3
Crystallin alpha 1 AD Rare9 Cataract 9 multiple types
Open angle glaucoma
CRYAB 123590
11q23.1
Crystallin alpha 2 AD, AR Rare9 Cataract 16 multiple types
Myofibrillar myopathy 2
Dilated cardiomyopathy 1II
Hypertrophic cardiomyopathy
CRYBA1 123610
17q11.2
Crystallin beta 1 AD Rare9 Cataract 10 multiple types
CRYBA2 600836
2q35
Crystallin beta 2 AD, AR Rare9 Cataract 42
CRYBA4 123631
22q12.1
Crystallin beta 4 AD Rare9 Cataract 23 multiple types
Primary angle-closure glaucoma
CRYBB1 600929
22q12.1
Crystallin beta B1 AD, AR Rare9 Cataract 17 multiple types
CRYBB2 123620
22q11.23
Crystallin beta B2 AD Rare9 Cataract 3 multiple types
CRYBB3 123630
22q11.23
Crystallin beta B3 AD, AR Rare9 Cataract 22
CRYGB 123670
2q33.3
Crystallin gamma-B AD Rare9 Cataratc 39 multiple types
CRYGC 123680
2q33.3
Crystallin gamma-C AD Rare9 Cataract 2 multiple types
CRYGD 123690
2q33.3
Crystallin gamma-D AD Rare9 Cataract 4 multiple types
CRYGS 123730
3q27.3
Crystallin gamma-S AD Rare9 Cataract 20 multiple types
CTDP1 604927
18q23
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
EPHA2 176946
1p36.13
Ephrin receptor A2 AD 4.7% in Australia 12 Cataract 6 multiple types
EYA1 601653
8q13.3
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
Otofaciocervical syndrome
FOXC1 601090
6p25.3
Transcription factor Forkhead box E3 AD Rare Anterior segment dysgenesis 3
Axenfeld-Rieger syndrome 3
FOXE3 601094
1p33
Transcription factor Forkhead box C2 AR 2.5% for MAC14 Anterior segment dysgenesis 2
Cataract 34 multiple types
Microphtalmia/Anophtalmia/coloboma (MAC)
FTL 134790
19q13.33
Ferritin light chain AD, AR 80% for Neuroferritinopathy 15 Hyperferritinemia-cataract syndrome
L-ferritin deficiency, dominant and recessive
Neurodegeneration with brain iron accumulation 3
FYCO1 607182
3p21.31
Transcription factor FYCO1 AR Rare Cataract 18
GALK1 604313
17q25.1
Galactokinese 1 AR Rare Galactokinase deficiency with cataracts
GCNT2 600429
6p24.3-p24.2
Glucosaminyl transferase 2 AD, AR Rare Cataract 13 with adult I phenotype
Adult I phenotype without cataract
GJA3 121015
13q12.11
GAP junction protein A3; Connexin 46 AD Rare Cataract 14 multiple type
GJA8 600897
1q21.2
GAP junction protein A8; Connexin 50 AD Rare Cataract 1 multiple type
HSF4 602438
16q22.1
Heat-shock transcription factor 4 AD 2/69 in Chinese population16 Cataract 5 multiple type
LEMD2 616312
6p21.31
Nuclear transmembrane protein 25 AR Rare Cataract 46 juvenile-onset
LIM2 154045
19q13.41
Lens intristic membrane protein 2 AR Rare Cataract 19 multiple types
LSS 600909
21q22.3
Lanosterol synthase AR Rare Cataract 44
MAF 177075
16q23.2
Transcription factor MAF AD Rare Cataract 21 multiple types
Ayme-Gripp syndrome
MIP 154050
12q13.3
Major lens intrinsic protein AD Rare Cataract 15 multiple type
NHS 300457
Xp22.2-p22.1
NHS actin remodeling regulator XLD Rare Cataract 40, X-linked
Nance-Horan syndrome
P3H2 610341
3q28
Prolyl 3-hydrolase AR Rare Myopia, high, with cataract and vitreoretinal degeneration
PAX6 607108
11p13
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
PITX3 602669
10q24.32
PAX6-regulated transcription factor 3 AD Rare Cataract 11 multiple types
Anterior segment dysgenesis 1, multiple subtypes
SIPA1L3 616655
19q13.1-q13.2
SIPA1-proliferation protein 3 AR Rare Cataract 45
SLC16A12 611910
10q23.31
Monocarboxylate transporter 12 AD Rare Cataract 47 with microcornea
TDRD7 611258
9q22.33
Tudor domain regulating protein 7 AR Rare Cataract 36
UNC45B 611220
17q12
Myosin-specific shaperone UNC45 AD Rare Cataract 43
VIM 193060
10p13
Vimentin AD Rare Cataract 30 pulverulent
VSX2 142993
14q24.3
Homeobox protein 10 AR Rare Microphthalmia with coloboma 3
Isolated microphthalmia-2
WFS1 606201
4p16.1
Wolframin AD, AR Rare Cataract 41
Wolfram syndrome
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.