Massively parallel sequencing and rare disease

Abstract

Massively parallel sequencing has enabled the rapid, systematic identification of variants on a large scale. This has, in turn, accelerated the pace of gene discovery and disease diagnosis on a molecular level and has the potential to revolutionize methods particularly for the analysis of Mendelian disease. Using massively parallel sequencing has enabled investigators to interrogate variants both in the context of linkage intervals and also on a genome-wide scale, in the absence of linkage information entirely. The primary challenge now is to distinguish between background polymorphisms and pathogenic mutations. Recently developed strategies for rare monogenic disorders have met with some early success. These strategies include filtering for potential causal variants based on frequency and function, and also ranking variants based on conservation scores and predicted deleteriousness to protein structure. Here, we review the recent literature in the use of high-throughput sequence data and its analysis in the discovery of causal mutations for rare disorders.

Figure 1.

Effect of increasing number of control exomes on private variants observed in a single exome, with and without the use of dbSNP and 1000 genomes data. The number of private mutations observed in an individual from sequential addition of control exomes was averaged from 10 000 permutations of 21 published exomes of non-African ancestry (9,13,16).