Comprehensive genomic analysis — complementing sequencing with high-resolution CNV detection

Ruth Burton and Ephrem Chin

Abstract

The sequencing of genes within clinical research laboratories to identify potentially causative mutations is an established technique. While both Sanger sequencing and next generation sequencing (NGS) present efficient technologies for detecting disease-linked variants, they are not standalone methods. Not all mutation types can be accurately detected, and this includes copy number variants, for which array comparative genomic hybridisation (aCGH) remains the gold standard. Rather than relying upon a single technology, researchers such as those at Emory Genetics Laboratory (EGL) are instead proposing an integrated approach, complementing sequencing with high-resolution aCGH, thereby providing a comprehensive picture of the disease. In line with this concept, EGL has established an ongoing collaboration with Oxford Gene Technology in order to guide the design of disease-specific molecular arrays, leveraging EGL’s clinical research experience. This white paper will discuss the role of these molecular arrays as part of their complete investigation framework, and how such an integrated approach presents the next stage of molecular testing in clinical genetics research. To provide real-world examples, this approach will also be discussed in the context of two case studies.

Introduction

Over the last few decades, it has become increasingly evident that genetic disorders are rarely caused by an isolated mutation within a single gene. In light of advances in DNA analysis technologies, we are instead witnessing a shift away from the ‘single mutation – single disorder’ paradigm, becoming ever more aware of the underlying genetic complexity. One or many genes can contribute to one or multiple disorders, which can give rise to a range of phenotypes, while the causal aberrations can vary widely from larger copy number variations (CNVs), down to single point mutations (Figure 1).

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