摘要：De novo mutations that contribute to rare Mendelian diseases, including neurological disorders, have been recently identified. Whole-exome sequencing (WES) has become a powerful tool for the identification of inherited and de novo mutations in Mendelian diseases. Two important guidelines were recently published regarding the investigation of causality of sequence variant in human disease and the interpretation of novel variants identified in human genome sequences. In this study, a family with supposed movement disorders was sequenced via WES (including the proband and her unaffected parents), and a standard investigation and interpretation of the identified variants was performed according to the published guidelines. We identified a novel de novo mutation (c.2327C > T, p.P776L) in DYNC1H1 gene and confirmed that it was the causal variant. The phenotype of the affected twins included delayed motor milestones, pes cavus, lower limb weakness and atrophy, and a waddling gait. Electromyographic (EMG) recordings revealed typical signs of chronic denervation. Our study demonstrates the power of WES to discover the de novo mutations associated with a neurological disease on the whole exome scale, and guidelines to conduct WES studies and interpret of identified variants are a preferable option for the exploration of the pathogenesis of rare neurological disorders.
