Abstract

Use of High-Throughput Sequencing for Disease Gene Discovery: the Path from Helix to Health

Wen-Hung Chung, Director, Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital

Although array-based genotyping methods for common variants have thus far succeeded in explaining a modest fraction of the genetic components of human diseases, recent advances in next-generation sequencing (NGS) technologies have rapidly facilitated substantial progress. This outcome is expected because NGS can directly identify the causal variants whereas chip-based platforms generally only capture a few percent of the estimated heritability for these diseases. With further developments in sequencing technologies for data acquisition and more effective tools for data analysis and clinical extraction, NGS now becomes technically feasible to search for Mendelian disease genes in an unbiased manner with strategies that depends on the availability of well-phenotyped patients and family members. Here, we show our attempts to uncover novel disease-causing mutations for rare hereditary diseases (e.g. hereditarily cutaneous diseases, rare neurological diseases, and inherited pediatric conditions) by whole-genome or whole-exome sequencing. In particular, we apply a more comprehensive approach to detect rare variants that contribute considerably to these conditions. Through unveiling the genetic basis of these disorders and the identification of new genes and pathways, a better understanding of disease pathogenesis is obtained, ultimately leading to the development of therapeutic strategies and accurate prediction of clinical outcome.