Genetic landscape of isolated pediatric cataracts: extreme heterogeneity and variable inheritance patterns within genes

Abstract

Pediatric cataract represents an important cause of pediatric visual impairment. While both genetic and environmental causes for pediatric cataract are known, a large proportion remains idiopathic. The purpose of this review is to discuss genes involved in isolated pediatric cataract, with a focus on variable inheritance patterns within genes. Mutations in over 52 genes are known to cause isolated pediatric cataract, with a major contribution from genes encoding for crystallins, transcription factors, membrane proteins, and cytoskeletal proteins. Interestingly, both dominant and recessive inheritance patterns have been reported for mutations in 13 different cataract genes. For some genes, dominant and recessive alleles represent distinct types of mutations, but for many, especially missense variants, there are no clear patterns to distinguish between dominant and recessive alleles. Further research into the functional effects of these mutations, as well as additional data on the frequency of the identified variants, is needed to clarify variant pathogenicity. Exome sequencing continues to be successful in identifying novel genes associated with congenital cataract but is hindered by the extreme genetic heterogeneity of this condition. The large number of idiopathic cases suggests that more genes and potentially novel mechanisms of gene disruption remain to be identified.

Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

“…In crystallin genes, non sense-mediated decay is determinant to whether the mutant alleles will have recessive or dominant effects. Thus, truncating mutations which appear in the initial coding sequences of the gene will be affected by non sense-mediated decay and follow a recessive pattern; whereas mutations in the final exon will be associated with dominant disease [ 16 ]. Mutations in crystallin genes accounted for the majority of hereditary congenital cataracts in our study (30%), which was an expected result as this is the most frequent mutation reported up to date.…”

“…Early intervention is crucial due to the high risk of amblyopia. Cataract surgery in babies and infants has a high risk of postoperative complications and it is a challenge to achieve a good visual acuity despite timely intervention and adequate follow-up [ 16 , 17 , 18 , 19 , 20 ].…”

Novel missense mutation of major intrinsic protein gene in congenital cataract

“…The utility of trifocal and extended depth of focus intraocular lenses in particular requires accurate centration to provide optimal visual outcomes and minimize photic phenomena such as glare and halo. [1][2][3] Angle kappa has been used as a measure of centration in both refractive and lens-based surgery. It is defined as the angle difference between the visual axis (theoretical axis connecting the point of fixation with the nodal points and the fovea) and pupillary axis (line perpendicular to the cornea that passes through the center of the pupil).…”

Variants in PAX6, PITX3 and HSF4 Causing Autosomal Dominant Congenital Cataract

“…Congenital cataract are clinically and genetically heterogeneous, displaying various phenotypes [1]. So far nearly 50 genes have been found causing mostly isolated congenital cataracts broadly including genes encoding lens soluble proteins -crystallins; membrane proteins-gap junctions, aquaporins, receptor tyrosine kinase gene EPH receptor A2, an endoplasmic reticulum membrane-embedded protein, Wolframin, chromatin modifying protein-4B, lens integral membrane protein; AQP0, Connexin 50 and LIM2 cytoskeletal proteins-filensin, phakinin, vimentin and genes encoding transcription or developmental factors EYA1, MAF, FOXE3, VSX2, PAX6, PITX3 and HSF4 (https :// cat-map.wustl.edu/) [2][3][4].…”