Increasing diagnostic yield of fast diagnostics using NGS

Supervisors

Pieter Neerincx and Gerben van der Vries

Introduction

Next Generation Sequencing (NGS) has become a very important tool for geneticists. At the UMCG we use NGS in wide range of applications ranging from sequencing gene panels (few dozen genes) via whole exome sequencing (WES) to whole genome sequencing (WGS).

The diagnostic yield (solved cases) varies a bit per application / disease type, but there are always unsolved cases. Our current bioinformatics analysis only considers single nucleotide variants (SNVs), short insertion/deletions (InDels) and large deletions. There may be various reasons why a case remains unsolved:

• The symptoms are not caused by a genetic disease: something else is going on.
• The genetic variant is part of a region that cannot be reliably sequenced.
• The genetic variant was sequenced, but is not yet called by our bioinformatics pipeline.
• The genetic variant was sequenced and called, but we cannot interpret the effect of the variant correctly.

Project 1 - Improved variant calling for DNA seq

In this student research project we will re-analyse 60 samples of unsolved cases sequenced with a Dystonia Gene Panel kit and test if we can increase the diagnostic yield for this group of patients. The samples were originally analysed with a now outdated version of the human reference genome GRCh37. We will focus on the impact of the using the updated human genome reference GRCh38 and in addition include mtDNA in the analysis,which was previously missed.