Genome diagnostics in transition: a paradigm shift in clinical genetic testing
Genome diagnostics in transition: a paradigm shift in clinical genetic testing
Genome diagnostics examines a patient’s DNA to identify genetic variants that may cause disease. These variants can be very small—just a single “letter” difference—or much larger, such as missing, extra, or rearranged segments. Detecting these variants is essential for diagnosis and to support reproductive planning. However, identifying all types of variants remains challenging and often requires complementary tests.
Over the past decade, NGS has become widely adopted in genetic testing. This technology enables simultaneous analysis of many genes and patients and it is particularly effective at detecting small variants, identifying low-frequency mutations, and assessing gene activity through RNA transcription. Despite these strengths, NGS also has limitations. NGS reads DNA in short fragments, making it challenging to reconstruct complex or repetitive regions using NGS data, and it is less reliable for detecting structural changes. Additionally, NGS cannot always determine whether a genetic change has been inherited from a patient’s mother or father.
Emerging technologies, such as long-read sequencing, allow analysis of much longer DNA stretches. This improves detection of complex and large-scale changes and may reduce the need for multiple tests.
This thesis of Eduard de Boer is divided into two main parts. The first part is focussed on improving NGS-based testing, including applications in prenatal and newborn screening, as well as the detection of very low levels of specific DNA- or RNA-copies. The second part is focussed on approaches aimed at improving genome diagnostics for inherited diseases and blood cancers with the goal of faster and more accurate diagnosis in the future.