Mathematical Model to Assess Mutational Burden in Retinal Dystrophy Patients Negative to Mendelian Genetic Tests and Carriers of Multiple Recessive Variants

Abstract

Abstract Purpose Despite advancements in genetic testing, a significant number of patients with retinal dystrophy receive negative test results due to single-allele mutations in genes with autosomal recessive inheritance patterns. This study aimed to address this diagnostic challenge by proposing a preliminary mathematical model based on mutational burden analysis. This approach can identify unique digenic or oligogenic combinations, potentially prioritizing them for further investigation. Methods We retrospectively analyzed clinical and genetic data from 527 subjects comprising 453 patients with retinal dystrophies (cases) and 74 controls and created semi-synthetic datasets. Protein–protein interaction networks were analyzed, and the significance of mutational burden in specific molecular pathways was investigated. Results Our model identified two metabolic pathways that are highly correlated to each other, namely “retinoid cycle disease events” and “canonical retinoid cycle in rods (twilight vision).” These pathways were significantly impacted by the burden of variants we found in the case group. Moreover, the gene combinations (ABCA4, RDH12) and (ABCA4, RBP3) were identified exclusively in cases of retinal dystrophies. Conclusion The proposed preliminary model provides a systematic approach to calculate the mutational burden in patients with retinal dystrophies and previous negative genetic test results. Moreover, the bioinformatic analysis facilitated the identification of recurrent combinations of involved genes, suggesting possible new digenic or oligogenic inheritance patterns.