Friday, April 4, 2025
4/4/2025
Finding Missing Genetic Causality of Inherited Retinal Degenerations - Project Summary/Abstract Understanding the functional consequences of rare variants of unknown significance (VUSs) is a major challenge in the field of human genetics and it is critical in genetic diagnostic testing in all fields of genomic medicine, including cancer, cardiology and all rare diseases. It affects the choice of adequate treatments, preventive measures, prognostics, and family planning. In this proposal we will study inherited retinal degenerations (IRDs) as a model of a rare disease in which the lack of definitive interpretation of VUSs greatly reduces genetic diagnostics, prognostics and access to the emerging genetic treatments. IRDs are important monogenic blinding diseases, caused by mutations in one of ~280 genes. The genetic diagnostic rate based on research testing is reported to be 65-70%. However, after applying the criteria of variant pathogenicity assessment used in clinical genetic testing, a third of the genetic diagnoses are based on VUSs, reducing the clinically relevant solutions to 50% of IRD cases. One way a variant can lead to disease is by causing aberrant pre-mRNA splicing, which is different from common cell-type specific alternative splicing. Variants that lead to aberrant splicing don’t always fall in the canonical splice sites and are often overlooked, as their effect on splicing is challenging to predict even with the machine learning algorithms developed for this purpose. We propose that rare coding or non-coding variants leading to splicing defects are an important contributor to the missing causality of rare diseases, including IRDs. To address this challenge, we developed a high throughput splicing assay (HTSA), which will be used in Aim 1. Another aspect of the missing genetic causality of rare diseases is related to the difficulties of detecting pathogenic complex structural variations Identification of new IRD genes has slowed significantly and represents small numbers of cases. However, detection of large deletions and duplications, or copy number variations, in the known IRD genes has shown a significant impact on the diagnostic rate (6-9% of genetic diagnoses). We hypothesize that extending these studies to include other types of structural variants (SVs), such as inversions, translocations or complex rearrangements will account for a significant proportion of currently elusive genetic causality. Therefore in Aim 2 we propose to perform a systematic survey of SVs in unsolved IRD families using short-read and long-read genome sequencing approaches. Results of the proposed studies will lead to new genetic diagnoses, which will enhance patients’ clinical care and will provide them with opportunities to participate in clinical trials of potential therapies and receive approved genetic treatments. Additionally it will shed light on how genomic variation affects gene function and leads to phenotypes, which is one of the central problems in biology.
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