Discovering the genetic cause of Mendelian disorders in the age of genomics: the evolving capability of next-generation DNA sequencing

The research presented in this thesis identifies the genetic cause of a diverse range of Mendelian disorders using next generation sequencing. This work reflects the extremely rapid development of NGS, beginning with target gene panel sequencing in a research setting (Chapters 2 and 3) and only 4 years later progressing to our evaluation of diagnostic yield if whole-exome sequencing is implemented in the clinic and when using whole-genome sequencing for our research (Chapters 7 and 8). These discoveries show the evolving capability of NGS to uncover the genetic cause of Mendelian disorders and the revolution upon healthcare occurring as a result of its application.

In Part I we utilize NGS to discover genetic variants in patients with rare phenotypes for which no genetic cause is known. In Chapter 2 and Chapter 3 we use a targeted gene panel sequencing approach to identify causal variants by including known genes involved in disease etiology and candidate genes that could play a role in development of disease. In Chapter 4 we move to a more comprehensive approach by utilizing WES to analyze the coding regions of all known protein coding genes and eventually establish a genetic diagnose for two brothers with Mohr syndrome.

In Part II we focus on rare metabolic diseases patients born of consanguineous parents and use regions of homozygosity to narrow our genetic search space for causal genes. We use targeted gene panel sequencing to evaluate all genes within the regions of homozygosity (Chapter 5) or identify candidate genes in those regions to Sanger sequence (Chapter 6).

Finally, in Part III we progress to the clinical utility of NGS by performing a study analyzing the diagnostic yield of trio-WES and concurrently evaluate cost savings if this technology was implemented early (Chapter 7). In Chapter 8 we discuss the state-of-art of NGS and its implications for the patient, the clinic, and society. The expanding scope and use of NGS will enable more patients to obtain faster diagnoses and remodel the healthcare system, though there are still challenges to address. Finally, the ability to sequence our own genomes will impact individuals with the possibility of “personal genomes”, including my own, and what this may mean for society.