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Case Reports
. 2016 Feb 5;6:20423.
doi: 10.1038/srep20423.

Identification of a De Novo DYNC1H1 Mutation via WES According to Published Guidelines

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Free PMC article
Case Reports

Identification of a De Novo DYNC1H1 Mutation via WES According to Published Guidelines

Dongxue Ding et al. Sci Rep. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1. Clinical features of the patients and the pedigree with the c.2327C> T, p.P776L mutation in DYNC1H1.
(A) Foot deformities (pes cavus) of the two patients. (B) Pedigree structure of the studied family. In the family, WES was performed in I:1, I:2, and II:3. (C) Electropherograms of the Sanger sequences of the DYNC1H1 c.2327C > T, p.P776L variant; II: 2 and II: 3 are heterozygous mutations. (D) The conservation of this variant among different species.

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