Data Analysis in Rare Disease Diagnostics

Abstract

Data Analysis in Rare Disease Diagnostics 1 IntroductionA draft human genome covering ~ 95% of the human genome was first released in 2000 1 . The sequence, commonly referred to as the human reference genome sequence, is a composite sequence created by sequencing and painstakingly assembling DNA obtained from anonymous volunteers of diverse backgrounds. This ~ 3 billion nucleotide-long genome sequence has undergone several revisions over the years and there are still small regions that have remained intractable. It is not an exaggeration to state that all clinical genomics applications today use the reference sequence as the basis for analysis.In this article, we focus on the topic of rare disease diagnosis through sequencing. There are over 8600 rare disease phenotypes documented in OMIM today 2 . The molecular basis for 6200 of these diseases has been traced to 3900 genes in the reference genome. Most rare diseases are caused by just one or two variants present in the patient genome. However, identifying the exact variants from among the more than 5 million small variants that distinguish any individual from the reference genome is an extremely challenging task 3 .There are four major steps in the rare disease diagnosis process-sequencing, variant detection, variant assessment, and variant prioritization. In this article, we take you through these steps explaining the data analysis that happens at each