Genetic Analysis Of A Spanish Retrospective Cohort With Early-Onset Bilateral Non-Syndromic Cataracts

Early-onset non-syndromic cataract is a rare genetic condition characterized by bilateral, symmetrical cataracts that develop at birth or in early childhood, without involvement of other organ systems. It is one of the leading causes of preventable childhood blindness worldwide. This study aims to identify the genetic factors responsible for early-onset non-syndromic cataracts within a retrospective cohort, highlighting novel potential disease-causing variants and providing a comprehensive analysis of their associated phenotypes.

This clinical and genetic single center cohort study was conducted at a tertiary hospital, recognized as one of the main referral centers for early-onset cataracts in Spain. The study included all patients under 18 years of age with congenital or progressive non-syndromic bilateral cataracts who underwent cataract surgery between the years 2016 and 2024.

Following ophthalmological evaluation and the collection of peripheral blood samples from participating families, next-generation sequencing (NGS) was conducted on the index patients. A comprehensive filtering process was then applied to identify potential disease-associated variants in genes previously linked to congenital cataracts. Subsequently, a segregation analysis was performed using targeted Sanger sequencing to determine the presence of the identified variants in the parents.

The study included 88 patients, with 60% male and 40% female probands. Among the cases, 36% were congenital. The most common cataract phenotype was nuclear (33.0%), followed by total (21.6%) and posterior subcapsular (15.9%). Additional ocular malformations were observed in 33% of patients. The overall positive genetic diagnosis rate was 55%, with 41% of variants classified as uncertain significance, 43% as likely pathogenic, and 16% as pathogenic. Genetic findings showed high heterogeneity: 32% of mutated genes were transcription factors, 21% encoded crystallins, and 21% were membrane transport proteins. Autosomal dominant inheritance was the most common inheritance pattern (78%), with 43% of mutations occurring de novo.

This study highlights the genetic diversity of early-onset non-syndromic cataracts, revealing a wide range of mutations across different gene categories in a Spanish retrospective cohort. It identifies distinct genotype-phenotype correlations and broadens the known genetic spectrum. The findings emphasize the importance of genetic testing in congenital cataracts, which is crucial for accurate diagnosis, counseling, and treatment planning. These results may provide valuable insights for the future development and consideration of targeted therapies for affected individuals.