Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts

Abstract

Non-syndromic pediatric cataracts are defined as opacification of the crystalline lens that occurs during the first years of life without affecting other organs. Given that this disease is one of the most frequent causes of reversible blindness in childhood, the main objective of this study was to propose new responsible gene candidates that would allow a more targeted genetic approach and expand our genetic knowledge about the disease. We present a whole exome sequencing (WES) study of 20 Spanish families with non-syndromic pediatric cataracts and a previous negative result on an ophthalmology next-generation sequencing panel. After ophthalmological evaluation and collection of peripheral blood samples from these families, WES was performed. We were able to reach a genetic diagnosis in 10% of the families analyzed and found genes that could cause pediatric cataracts in 35% of the cohort. Of the variants found, 18.2% were classified as pathogenic, 9% as likely pathogenic, and 72.8% as variants of uncertain significance. However, we did not find conclusive results in 55% of the families studied, which suggests further studies are needed. The results of this WES study allow us to propose LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, and CHMP4A as potential candidates to further investigate for their role in pediatric cataracts, and AQP5 and locus 2q37 as causal genes.

Effect of clinical whole exome sequencing in aetiological investigation and reproductive risk prediction for a couple with monogenic inherited diseases

“…Additionally, different variants in β-crystallin genes can cause different types of cataracts, including variants in the β-B3 crystallin gene ( CRYBB3 ; OMIM 123630), which cause Cataract 22 (OMIM 609741). As of 3 October 2022, the Cat-Map website has included data on 10 CRYBB3 gene variant loci, including 7 AD genetic loci: c.75 + 1G>A ( Chen and Zhu, 2021 ), c.224G>A ( Rodríguez-Solana et al, 2023 ), c.466G>A ( Taylan Sekeroglu et al, 2020 ), c.467G>A ( Zin et al, 2021 ), c.531G>T ( Fernández-Alcalde et al, 2021 ), c.581T>A ( Xu et al, 2021 ), and c.634T>C ( Fan et al, 2020 ), as well as 1 AR genetic locus, c.493G>C ( Iqbal et al, 2020 ).…”

Through the Cat-Map Gateway: A Brief History of Cataract Genetics

“…VUS: Finally, in addition to mutations in known genes for cataract, variants of unknown significance (VUS) in the genes for ATP binding cassette subfamily B member 6 ( ABCB6 ), acetyl-CoA carboxylase α/1 ( ACACA ), charged multivesicular body protein 4A ( CHMP4A ), chloride intracellular channel protein 5 ( CLIC5 ), heat shock protein family E (Hsp10) member 1 ( HSPE1 ), outer dense fiber of sperm tails 1 ( ODF1 ), and transient receptor potential cation channel subfamily melastatin, member 1 ( TRPM1 ) have been associated with non-syndromic (likely autosomal dominant), congenital cataract (including nuclear, lamellar, posterior subcapsular/polar, and pulverulent opacities) in a cohort of Spanish families—and these await further validation as cataract-causing mutations [ 156 , 157 ].…”