Nowadays, genetic testing can provide an accurate diagnosis for hereditary disorders in general practice. Currently, the accumulation of variants of unknown significance (VUSs) during genetic testing is a major problem and rate-limiting step in genetic diagnosis. This study provides a novel and high-throughput methodology to solve this problem and promotes rapid evaluations of VUSs. Further comprehensive analysis of RNA and proteins in conjunction with DNA can also provide a faster and more accurate diagnosis. Although this study focuses on ECHS1 gene, this is a scalable methodology that can be extended to other mitochondrial diseases or inborn errors of metabolism. (By Dr. Yasushi Okazaki, https://jmg.bmj.com/content/early/2023/04/12/jmg-2022-109027 )