Using whole exome sequencing to identify mutations of four different human diseases

Abstract

Whole exome sequencing (WES) is an application of the next generation sequencing (NGS). With this technique, the target regions such as coding sequences, splice site, non-coding RNA and highly conserved regions which are about 1 percent of the genome harboring about 85 percent of mutations with large effects on disease-related traits are sequenced. Here, two different Mendelian disorders were studied. The first is familial comedones, a rare autosomal dominant skin disorder. Two unrelated families affected with familial comedones were included. WES combined with whole genome linkage analysis using a single nucleotide polymorphism (SNP) array was conducted in the first family which identified a heterozygous mutation, c.84_85insT in the PSENEN gene. This mutation was also identified in the second family. Quantitative real-time PCR indicated increased expression of PSENEN mRNA in the patients. Another disease included in this study is an undiagnosed syndrome with intellectual disability in a non-consanguineous family. Two siblings were affected. Exome sequencing was performed in both patients and their parents. Neither pathogenic copy number variations nor SNVs/indels were identified. In summary, conducting WES led us to identify a novel gene underlying familial comedones. However, using WES to find a gene underlying a disease with genetic heterogeneity as intellectual disability remains a challenge.