SEARCHCASE_REPORTophthalmology, pediatric ophthalmology

case_report·ophthalmology, pediatric ophthalmology, genetics, cataract surgery·PMC10380485

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

International Journal of Molecular Sciences · 19 authors, 6 centres

AI SUMMARY

FIDELITY 100%

POPULATION23 affected children from 20 unrelated Spanish families with non-syndromic pediatric cataracts, negative for a 39-gene panel

INTERVENTIONWhole exome sequencing (WES) with CNV analysis

COMPARISONNot applicable (no control group; family-based segregation analysis)

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TL;DR

Whole exome sequencing of 20 Spanish families with non-syndromic pediatric cataracts identified a definitive genetic diagnosis in 10% of families (AQP5 mutation and 2q37.3 deletion) and proposed eight candidate genes in 35% of families. The study highlights the genetic heterogeneity of pediatric cataracts and the need for further functional studies to confirm candidate genes. These findings may improve genetic counseling and clinical management for affected families.

Full summary

2,721 CHARS

**Background:** Pediatric cataracts are a leading cause of preventable childhood blindness, with an incidence of 1.8–3.6/10,000 per year. Hereditary cases account for 25% of pediatric cataracts, and non-syndromic forms are genetically heterogeneous, with over 56 genes and 71 loci identified. Despite known genes, many families remain undiagnosed. This study aimed to identify novel candidate genes for non-syndromic pediatric cataracts using whole exome sequencing (WES) in a Spanish cohort.

**Methods:** Twenty unrelated Spanish families (23 affected children) with non-syndromic bilateral or unilateral pediatric cataracts were recruited from La Paz University Hospital. All had negative results on a targeted panel of 39 known cataract genes. WES was performed on genomic DNA from peripheral blood, using Illumina Nextera DNA Exome capture and sequencing on HiSeq4000/NovaSeq6000. Bioinformatics analysis identified SNPs, indels, and CNVs. Variants were classified according to ACMG guidelines. Ophthalmological data included cataract type, laterality, microphthalmia, nystagmus, age at surgery, and postoperative glaucoma.

**Key Results:** Among 23 patients (45 eyes), the most common cataract types were nuclear (12 eyes) and lamellar (12 eyes). Lensectomy was performed in 28 eyes; 16 (59%) were operated before age 1 year. Postoperative glaucoma occurred in 6 eyes, nystagmus in 8 eyes, and microphthalmia in 10 eyes.

WES yielded a definitive genetic diagnosis in 10% (2/20) of families: a de novo missense variant in AQP5 (NM_001651.3:c.152T>C:p.(Leu51Pro)) in family OFT-00040, and a de novo 661.2 kb deletion at 2q37.3 in family OFT-00350. Both were classified as pathogenic.

In 35% (7/20) of families, candidate genes were identified: LONP1 (VUS, missense), ACACA (VUS, missense), TRPM1 (likely pathogenic, frameshift), CLIC5 (VUS, missense), HSPE1 (VUS, frameshift) and ODF1 (VUS, in-frame deletion) in the same proband, PIKFYVE (VUS, splicing), and CHMP4A (VUS, biallelic nonsense and frameshift). In 55% (11/20) of families, no conclusive variants were found.

**Clinical Implications:** This study confirms the utility of WES in diagnosing pediatric cataracts, achieving a 10% diagnostic rate in a cohort pre-screened with a targeted panel. The identification of AQP5 and 2q37.3 deletions as causative reinforces their role in cataractogenesis. The eight proposed candidate genes (LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, CHMP4A) expand the genetic landscape of non-syndromic pediatric cataracts. Functional studies and replication in larger cohorts are needed to confirm causality. These findings may improve genetic counseling, prognostication, and early intervention for affected families.

PICO

PPOPULATION

23 affected children from 20 unrelated Spanish families with non-syndromic pediatric cataracts, negative for a 39-gene panel

IINTERVENTION

Whole exome sequencing (WES) with CNV analysis

OOUTCOME

Identification of pathogenic/likely pathogenic variants and candidate genes for pediatric cataracts

STUDY TYPE

case_report

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10380485

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

International Journal of Molecular Sciences

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ABSTRACT

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. Keywords: non-syndromic pediatric cataracts, bilateral cataracts, lenses, whole exome sequencing, ophthalmogenetics

CITATION EXPORT

Patricia Rodríguez-Solana, Natalia Arruti, María Nieves-Moreno et al.. Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms241411429

AUTHORS

19 · 6 CENTRES

Patricia Rodríguez-Solana, Natalia Arruti, María Nieves-Moreno, Rocío Mena, Carmen Rodríguez-Jiménez, Marta Guerrero-Carretero, Juan Carlos Acal, Joana Blasco, Jesús M Peralta, Ángela Del Pozo, Victoria E F Montaño, Lucía De Dios-Blázquez, Celia Fernández-Alcalde, Carmen González-Atienza, Eloísa Sánchez-Cazorla, María de Los Ángeles Gómez-Cano, Luna Delgado-Mora, Susana Noval, Elena Vallespín

1Molecular Ophthalmology Section, Institute of Medical and Molecular Genetics (INGEMM), IdiPaz, La Paz University Hospital, 28046 Madrid, Spain; [email protected] (P.R.-S.); [email protected] (R.M.); [email protected] (C.R.-J.); [email protected] (V.E.F.M.); [email protected] (C.G.-A.); [email protected] (E.S.-C.)
2Department of Pediatric Ophthalmology, IdiPaz, La Paz University Hospital, 28046 Madrid, Spain; [email protected] (N.A.); [email protected] (M.N.-M.); [email protected] (M.G.-C.); [email protected] (J.C.A.); [email protected] (J.B.); [email protected] (J.M.P.); [email protected] (C.F.-A.); [email protected] (S.N.)
3European Reference Network on Eye Diseases (ERN-EYE), La Paz University Hospital, 28046 Madrid, Spain
4Biomedical Research Center in the Rare Diseases Network (CIBERER), Carlos II Health Institute (ISCIII), 28029 Madrid, Spain; [email protected] (Á.D.P.); [email protected] (M.d.L.Á.G.-C.); [email protected] (L.D.-M.)
5Clinical Bioinformatics Section, Institute of Medical and Molecular Genetics (INGEMM), IdiPaz, CIBERER, La Paz University Hospital, 28046 Madrid, Spain; [email protected]
6Clinical Genetics Section, Institute of Medical and Molecular Genetics (INGEMM), IdiPaz, CIBERER, La Paz University Hospital, 28046 Madrid, Spain