Abstract

Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of “Epilepsy”, which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.

Highlights

  • Guidelines for investigating Focus on investigating causality of sequence causality of sequence variants in human disease variants in human disease

  • Our data demonstrated that Trio-Whole-exome sequencing (WES), combined with the objective interpretation of sequencing variants, is a preferable strategy to explore the genetics of human disease

  • The average frequency of the seizures were 1–3 times per day before the treatment, it could reach to 8 times in some days

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Summary

Introduction

Guidelines for investigating Focus on investigating causality of sequence causality of sequence variants in human disease variants in human disease. We used Trio-WES (including the proband and the unaffected parents) and the related guidelines (Table 1) to explore them in Chinese population, and identified three novel mutations in ADSL gene in two Chinese families, and refined the diagnosis from “Epilepsy” to “Adenylosuccinate Lyase Deficiency”. This is the first report of ADSL mutations in Chinese population, which expanded the mutations spectrum of this gene. Our data demonstrated that Trio-WES, combined with the objective interpretation of sequencing variants, is a preferable strategy to explore the genetics of human disease

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