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DE
16 January 2020
Mitochondrial disorders belong to the most frequently occurring metabolic disorders (incidence estimated 1:5000 live births). The disease onset can be at any age, involving different organs, and with a wide range of clinical signs and symptoms. Establishing a diagnosis is often challenging because of the large number of mitochondrial disease-causing genes (approximately 400 disease-causing genes described to date) and very limited genotype-phenotype correlations.
In the Radboud Center for Mitochondrial Medicine, Whole Exome Sequencing (WES) is used to identify pathogenic genetic variants in patients suspected of a mitochondrial disorder. Based on genetic, clinical, and biochemical data, a diagnosis is made. However, proving a causal relationship between the patient’s phenotype and genetic variants of unknown significance (VUS) is difficult. The current procedures for follow-up investigations to prove causality are time consuming and do not always give clear answers.With this funding we will attempt to optimize the ability to study the causality between VUSs that have been identified in patients and mitochondrial function by using CRISPR/Cas9. With this gene-editing technique, we will repairing the genetic variant in patient fibroblasts restores mitochondrial function. Based on this we can conclude whether the VUS is pathogenic. We postulate that this technique will increase the number of VUSs that can be resolved, improving the diagnostics of mitochondrial disorders and ultimately of other metabolic diseases.
Mitochondrial disorders belong to the most frequently occurring metabolic disorders (incidence estimated 1:5000 live births). The disease onset can be at any age, involving different organs, and with a wide range of clinical signs and symptoms. Establishing a diagnosis is often challenging because of the large number of mitochondrial disease-causing genes (approximately 400 disease-causing genes described to date) and very limited genotype-phenotype correlations.
In the Radboud Center for Mitochondrial Medicine, Whole Exome Sequencing (WES) is used to identify pathogenic genetic variants in patients suspected of a mitochondrial disorder. Based on genetic, clinical, and biochemical data, a diagnosis is made. However, proving a causal relationship between the patient’s phenotype and genetic variants of unknown significance (VUS) is difficult. The current procedures for follow-up investigations to prove causality are time consuming and do not always give clear answers.With this funding we will attempt to optimize the ability to study the causality between VUSs that have been identified in patients and mitochondrial function by using CRISPR/Cas9. With this gene-editing technique, we will repairing the genetic variant in patient fibroblasts restores mitochondrial function. Based on this we can conclude whether the VUS is pathogenic. We postulate that this technique will increase the number of VUSs that can be resolved, improving the diagnostics of mitochondrial disorders and ultimately of other metabolic diseases.
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