Summary
Recommended panel testing at Breda Genetics for this condition:
or
Isolated congenital cataracts are a common major abnormality of the eye that frequently cause visual impairment in infants. Infantile cataracts are treatable, but, if left untreated in infancy or childhood, they can result in irreversible amblyopia. The causes of congenital cataracts include intrauterine embryopathies and, in at least one third of cases, genetic defects. The most common form of hereditary cataracts in the Western world is autosomal dominant. However, also autosomal recessive and X-linked forms have been reported.
Detailed clinical features
Autosomal dominant cataract has been classified on the bases of the morphology, size, color, and location of the opacities in the lens, or the name of the author. Some of the clinical types recognized thus far are:Â congenital, zonular pulverulent, nuclear progressive, nuclear pulverulent, stellate nuclear, nuclear total, total, Coppock-like, embryonic, fetal, infantile nuclear, laminar, lamellar, fan-shaped, congenital cerulean, ‘blue dot,’ sutural with punctate and cerulean opacities, pulverulent embryonal, pulverulent with cortical opacities, dense posterior star-shaped subcapsular with pulverulent opacities in the cortical and embryonal regions, dense embryonal, posterior subcapsular congenital cataracts, aculeiform, crystalline aculeiform, crystalline, crystal, frosted, needle-shaped, fasciculiform, congenital cerulean, Y-sutural, nonnuclear polymorphic congenital, central nuclear, age-related cortical, anterior polar, Marner-type, nuclear coralliform and punctate.
In some cases, patients may also exhibit microcornea.
Autosomal dominant cataracts exhibit high penetrance and extreme clinical variability (the same phenotype may be caused by mutations in different genes; conversely, the identical mutation of a gene can cause different cataracts in different families). Congenital cataracts may be unilateral or bilateral and there can be considerable interocular asymmetry in morphology, density, location, and rate of progression. Age of onset is also variable. By definition, simple autosomal dominant cataracts have no associated systemic abnormalities.
Molecular genetics
Isolated hereditary cataracts are annotated in the OMIM database with the acronym CTRCT. Several genetic subtypes have been so far cloned, each of them associating to mutations in a different gene. For some genetic subtypes only the chromosomal locus was identified (no gene yet). In few cases, additional clinical signs are found in association to the presence of cataract.
CTRCT1 is caused by mutation in the GJA8 gene. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the GJA8 gene. From zonular pulvurent to posterior subcapsular, mutations in the GJA8 gene have been found to cause several clinical subtypes of cataract. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the GJA8 gene.
CTRCT2 is caused by mutation in the CRYGC gene and can be Coppock-like, embryonic, fetal, infantile nuclear; zonular pulverulent; and lamellar. Some patients also exhibit microcornea.
CTRCT3 is caused by heterozygous mutation in the beta-B2-crystallin gene (CRYBB2). The clinical subtypes associated to CRYBB2 mutations include congenital cerulean, ‘blue dot,’ Coppock-like, sutural with punctate and cerulean opacities, pulverulent embryonal, pulverulent with cortical opacities, dense posterior star-shaped subcapsular with pulverulent opacities in the cortical and embryonal regions, and dense embryonal.
CTRCT4 is caused by mutations in the CRYGD gene, CTRCT5 by mutations in the HSF4 gene, CTRCT6 by mutations in the EPHA2 gene, CTRCT9 by mutation in the CRYAA gene (both autosomal dominant and autosomal recessive modes of inheritance have been reported), CTRCT10 by mutations in the CRYBA1 gene, CTRCT11 by mutation in the PITX3 gene (two forms of CTRCT11 have been described: one form with isolated cataract and one syndromic form with microphthalmia and neurodevelopmental abnormalities), CTRCT12 is caused by mutations in the BFSP2 gene; CTRCT13 (which is autosomal recessive and is also known as cataract 13 with adult i phenotype) is caused by mutation in the homozygous or compound heterozygous mutations in the GCNT2 gene, CTRCT14 is caused by mutation in the GJA3 gene; CTRCT15 is caused by mutation in the MIP gene, CTRCT16 by mutation in the CRYAB gene, CTRCT17 by mutation in the CRYBB1 gene (both autosomal dominant and autosomal recessive forms have been described); CTRCT18 (which is autosomal recessive) is caused by mutations in the FYCO1 gene; CTRCT19 by mutation in the LIM2 gene; CTRCT20 by heterozygous mutation in the CRYGS gene; CTRCT21 is caused by mutation in the MAF gene (in some cases the onset is juvenile); CTRCT22 is caused by mutation in the CRYBB3 (both autosomal dominant and autosomal recessive heredity have been observed), CTRCT23 is caused by mutation in the CRYBA4 gene, CTRCT31 is caused by mutation in the CHMP4B gene, CTRCT33 (which is autosomal recessive) is caused by two mutations in the BFSP1 gene; CTRCT36 (also autosomal recessive and associated to other clinical signs such as hypospadias) is caused by mutations in the TDRD7 gene; autosomal recessive cataract-38 (CTRCT38) is caused by homozygous mutation in the AGK gene (of which mutations also cause Sengers syndrome, a syndromic form of congenital cataract with hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis).
CTRCT40 is inherited in an X-linked dominant fashion, being caused by mutation in the NHS gene (of which mutations also cause Nance-Horan syndrome). Males affected with CTRCT40 may exhibit lamellar, zonular, or perinuclear cataracts, with severe visual impairment and pronounced microcornea. Heterozygous females with CTRCT40 may have posterior suture or posterior stellate cataracts, or a combination of the two, with normal or slight reduction in vision.
Unconfirmed (because found in one family only) genetic subtypes of congenital cataract include CTRCT30, thought to be caused by mutation in the VIM gene; CTRCT41, thought to be caused by heterozygous mutation in the WFS1 gene; CTRCT42 (incomplete penetrance and variable association with myopia and glaucoma), thought to be caused by mutation in the CRYBA2 gene; and CTRCT43 (UNC45B gene mutations).
CTRCT44 is caused by homozygous mutation in the LSS gene. CTRCT45 is caused by homozygous mutation in the SIPA1L3 gene. Juvenile onset CTRCT46 is caused by mutation in the LEMD2 gene.
Apart from the aforementioned subtypes of isolated congenital cataracts, several other genetic subtypes have been cloned to certain chromosomal loci where mutations are falling in as yet unidentified genes. Hence, the genetic heterogeneity of congenital cataracts appears to be marked and the mutation remains undetected in a proportion of clinically affected patients.
In 2017, two additional genes for autosomal recessive nonsyndromic cataract have been identified: TAPT1 and WDR87.
Genetic testing strategy
Given the marked genetic heterogeneity of congenital isolated cataracts, panel testing based on exome sequencing or whole genome sequencing are highly recommended. Whole exome sequencing on trios (patient plus mother and father) may be useful in detecting a de novo mutation in an as yet unknown gene.
Recommended panel testing at Breda Genetics for this condition:
or
References:
Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract. Patel N, Anand D, Monies D, Maddirevula S, Khan AO, Algoufi T, Alowain M, Faqeih E, Alshammari M, Qudair A, Alsharif H, Aljubran F, Alsaif HS, Ibrahim N, Abdulwahab FM, Hashem M, Alsedairy H, Aldahmesh MA, Lachke SA, Alkuraya FS. Hum Genet. 2017 Feb;136(2):205-225. PMID: 27878435
Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis. Messina-Baas O, Cuevas-Covarrubias SA. Mol Syndromol. 2017 Mar;8(2):58-78. PMID: 28611546
Molecular genetics of congenital nuclear cataract. Deng H, Yuan L. Eur J Med Genet. 2014 Feb;57(2-3):113-22. PMID: 24384146
OMIM:Â 116200
