1. NGS panel - Genetic testing for cataract

Cataract

April 06, 2018

Disease summary:

Cataract refers to the clouding of the lens in the eye, defined as opacification of the normally transparent crystalline lens. Cataracts are common in older people and usually related to aging. They can be classified by the age at onset as congenital or infantile (<1yr); juvenile cataract (1-10yrs); presenile cataract (<45yrs) and senile or age-related cataract (>45yrs)1.

It is important to determine if the individual has non-syndromic (only the lens are affected) or syndromic (other organs in addition to the lens are affected) congenital cataracts. The most common causes of non-syndromic congenital cataracts are pathogenic variants in lens crystallin - associated genes (CRYAA, CRYAB, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD) which account for ~50% of all cases1, 2, 4


Autosomal dominant, autosomal recessive

1-6/10,000 for congenital cataract1; 1-15/10,000 in children 1, 3.

Major signs and symptoms of cataracts include 1, 3, 4:

  • 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
  • Visual acuity test.
  • Slit-lamp examination.
  • Retinal exam.
  • Diagnosis is confirmed by the finding of pathogenic variant in one of the following 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.

The only effective treatment for cataracts is surgery 1, 2.

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

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for cataract using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering 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 in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with early onset of cataracts.
  • Individuals with a positive family history of cataract.
  • Individuals with most common symptoms suggestive of cataracts (regardless of family history).

Confirmation of a clinical diagnosis through genetic testing of cataract can allow for genetic counseling and may direct medical management.


Table 1: Overview of genes included in Cataract panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
AGK 610345 Sengers syndrome; Cataract 38, autosomal recessive AR 4
BCOR 300485 Microphthalmia, syndromic 2 XL D 7
BFSP1 603307 Cataract 33, multiple types AD, AR 1
BFSP2 603212 Cataract 12, multiple types AD 0
CHMP4B 610897 Cataract 31, multiple types AD 0
CRYAA 123580 Cataract 9, multiple types AD, AR 1
CRYAB 123590 Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related; Cardiomyopathy, dilated, 1II AD, AR 1
CRYBA1 123610 Cataract 10, multiple types AD 0
CRYBA2 600836 ?Cataract 42 AD 0
CRYBA4 123631 Cataract 23 0
CRYBB1 600929 Cataract 17, multiple types AD, AR 4
CRYBB2 123620 Cataract 3, multiple types AD 0
CRYBB3 123630 Cataract 22 AD, AR 1
CRYGB 123670 Cataract 39, multiple types, autosomal dominant AD 0
CRYGC 123680 Cataract 2, multiple types AD 1
CRYGD 123690 Cataract 4, multiple types AD 0
CRYGS 123730 Cataract 20, multiple types AD 0
CTDP1 604927 Congenital cataracts, facial dysmorphism, and neuropathy AR 28
EPHA2 176946 Cataract 6, multiple types AD 2
EYA1 601653 Branchiootorenal syndrome 1, with or without cataracts; ?Otofaciocervical syndrome; Anterior segment anomalies with or without cataract; Branchiootic syndrome 1 AD 2
FOXC1 601090 Anterior segment dysgenesis 3, multiple subtypes; Axenfeld-Rieger syndrome, type 3 AD 6
FOXE3 601094 Anterior segment dysgenesis 2, multiple subtypes; Cataract 34, multiple types; Aortic aneurysm, familial thoracic 11, susceptibility to AD, AR 1
FTL 134790 Hyperferritinemia-cataract syndrome; Neurodegeneration with brain iron accumulation 3; L-ferritin deficiency, dominant and recessive AD, AR 4
FYCO1 607182 Cataract 18, autosomal recessive AR 10
GALK1 604313 Galactokinase deficiency with cataracts AR 4
GCNT2 600429 Adult i phenotype without cataract; [Blood group, Ii]; Cataract 13 with adult i phenotype AD, AR 6
GJA3 121015 Cataract 14, multiple types AD 0
GJA8 600897 Cataract 1, multiple types AD 2
HSF4 602438 Cataract 5, multiple types AD 2
LEMD2 616312 Cataract 46, juvenile-onset AR 0
LIM2 154045 Cataract 19, multiple types AR 7
LSS 600909 Cataract 44 AR 0
MAF 177075 Ayme-Gripp syndrome; Cataract 21, multiple types AD 1
MIP 154050 Cataract 15, multiple types AD 0
NHS 300457 Cataract 40, X-linked; Nance-Horan syndrome XL, XL D 6
P3H2 610341 Myopia, high, with cataract and vitreoretinal degeneration AR 0
PAX6 607108 Aniridia; Cataract with late-onset corneal dystrophy; ?Coloboma, ocular; ?Coloboma of optic nerve; ?Morning glory disc anomaly; Foveal hypoplasia 1; Keratitis; Optic nerve hypoplasia; Anterior segment dysgenesis 5, multiple subtypes AD 18
PITX3 602669 Anterior segment dysgenesis 1, multiple subtypes; Cataract 11, multiple types; Cataract 11, syndromic AD 0
SIPA1L3 616655 ?Cataract 45 AR 0
SLC16A12 611910 Cataract 47, juvenile, with microcornea AD 0
TDRD7 611258 Cataract 36 AR 7
UNC45B 611220 ?Cataract 43 AD 2
VIM 193060 Cataract 30, pulverulent AD 0
VSX2 142993 Microphthalmia with coloboma 3; Microphthalmia, isolated 2 5
WFS1 606201 ?Cataract 41; Diabetes mellitus, noninsulin-dependent, association with; Wolfram syndrome 1; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome, autosomal dominant AD, AR 16