Multimorbidity Through the Lens of the Eye: Pathogenic Variants for Multiple Systemic Disorders Found in an Autosomal Dominant Congenital Cataract Cohort

Berry, Vanita; Ponnekanti, Manav B.; Aychoua, Nancy; Ionides, Alex; Tsika, Chrysanthi; Quinlan, Roy A.; Michaelides, Michel

Abstract

Background: This paper will identify the potential genetic causes of multimorbidity associated with autosomal dominant congenital cataract (ADCC). Methods: Whole exome sequencing (WES) was performed on 13 individuals affected with ADCC. Subsequent bioinformatic analyses identified variants with deleterious pathogenicity scores. Results: Disease-causing variants were identified in 8 genes already linked to cataract (CHMP4B, CRYAA, CRYBA1, CRYGD, CYP21A2, GJA8, OPA1, and POMGNT1), but variants previously associated with systemic disorders were also found in a further 11 genes (ACTL9, ALDH18A1, CBS, COL4A3, GALT, LRP5, NOD2, PCK2, POMT2, RSPH4A, and SMO). All variants were identified via pipeline data analysis, prioritising rare coding variants using Kaviar and the Genome Aggregation Database. The following ADCC-associated non-ocular phenotypes were identified in four patients in the cohort: (i) Horner’s pupils, vaso-vagal syncope, and paroxysmal orthostatic tachycardia syndrome; (ii) reduced kidney function and high cholesterol; (iii) hypertension, high cholesterol, and kidney stones; and (iv) grade 1 spondylolysis. Conclusions: We report 11 novel genes identified in an ADCC patient cohort associated with systemic disorders found, along with 8 known cataract-causing genes. Our findings broaden the spectrum of potentially cataract-associated genes and their related lens phenotypes, as well as evidence multimorbidities in four patients, highlighting the importance of careful multisystem phenotyping following genetic analysis.

Citation

Berry, V., Ponnekanti, M. B., Aychoua, N., Ionides, A., Tsika, C., Quinlan, R. A., & Michaelides, M. (2025). Multimorbidity Through the Lens of the Eye: Pathogenic Variants for Multiple Systemic Disorders Found in an Autosomal Dominant Congenital Cataract Cohort. Genes, 16(5), Article 604. https://doi.org/10.3390/genes16050604

• Journal Article Type: Article
• Acceptance Date: May 19, 2025
• Online Publication Date: May 20, 2025
• Publication Date: 2025-05
• Deposit Date: May 21, 2025
• Publicly Available Date: May 21, 2025
• Journal: Genes
• Electronic ISSN: 2073-4425
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 5
• Article Number: 604
• DOI: https://doi.org/10.3390/genes16050604
• Public URL: https://durham-repository.worktribe.com/output/3956959