The Genetic Landscape of Paediatric Cataract in Saudi Arabia: A Two-Decade Cohort with Novel Variants, Genotype–Phenotype Correlations, and Bioinformatic Analysis

<b>Background/Objectives:</b> Paediatric cataract is among the most common treatable causes of childhood blindness, caused by a genetically diverse disorder with variable clinical features. Although genetic factors significantly contribute to the development of paediatric cataracts, recent data on their genetic makeup and genotype-phenotype relationships in Saudi Arabia is limited. This study aims to investigate the genetic spectrum, inheritance patterns, and genotype-phenotype correlations of paediatric cataract in a Saudi population over twenty years. <b>Methods:</b> We conducted a retrospective cohort study of children diagnosed with congenital or juvenile cataracts between 2000 and 2019 at two major referral centres in Riyadh. Clinical, ocular, and systemic data were collected through multidisciplinary evaluations. Genetic analysis involved whole-exome and whole-genome sequencing performed at College of American Pathologists (CAP)-accredited laboratories. Variant interpretation was supported by bioinformatic and Artificial Intelligence (AI) prediction tools. Genotype-phenotype relationships were systematically analysed. <b>Results:</b> The study included 28 cases of genetically confirmed paediatric cataracts. Variants classified as pathogenic or likely pathogenic were identified in 13 genes. Autosomal recessive inheritance was predominant, with many patients exhibiting homozygous variants, often due to consanguinity. Two novel variants were identified in the Collagen Type XVIII Alpha 1 Chain (<i>COL18A1</i>) and the RAB3 GTPase-activating protein catalytic subunit 2 (<i>RAB3GAP2</i>) genes. Considerable phenotypic variability was observed, even among patients with the same mutation, particularly those with the recurrent CRYBB1 c.171del (p.Asn58fs) mutation. Syndromic cataracts were more frequently associated with loss-of-function variants and multisystem features. <b>Conclusions:</b> This study offers updated insights into the genetics and clinical presentation of paediatric cataract in Saudi Arabia. It highlights high genetic diversity, unique inheritance patterns, and notable genotype-phenotype variability, emphasising the importance of early genetic testing and multidisciplinary assessment for improved diagnosis, management, and counselling.