Exploring the secondary use of clinical next generation sequencing data

Abstract

The application of next-generation sequencing (NGS) has been increasing rapidly. Besides providing the clinical diagnosis, further uses for the genetic data are increasingly sought. This dissertation aimed to explore the secondary use of the clinical NGS data on three areas: pharmacogenomics, actionable incidental findings, and carrier screening.

First, secondary analysis of exome sequencing (ES) data was conducted to study pharmacogenetics in a HK Chinese population of 1,116 subjects. The projected prescription impact by preemptive pharmacogenetic testing was evaluated based on the patient prescription data available in the HK public healthcare system for 2019. In this cohort, 29 actionable pharmacogenetic variants and alleles were identified. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, with a median of four, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant, with a median of two. The highest frequency of actionable genotypes was in recipients of clopidogrel (57.2%), tacrolimus (43.4%), and warfarin (43.1%). It was estimated that 13.4% of the HK population was prescribed with drugs with implicated actionable pharmacogenotypes according to the prescription data from the public healthcare system for 2019. The total expenditure on actionable drugs was US$33,520,000, and it was projected that patients having an implicated actionable genotype had been prescribed US$8,219,000 (24.5%) worth of drugs.

Second, the evaluation of actionable incidental findings was performed by using a recommended list of 59 genes suggested by the American College of Medical Genetics and Genomics. A total of 15 (1.52%) pathogenic or likely pathogenic variants were identified in 17 individuals in this cohort. None of the subjects in this cohort harbored any biallelic mutations in the same gene despite 20 subjects harboring pathogenic or likely pathogenic variants in recessive conditions. This finding that about 1% individuals harbored medically actionable incidental findings was in accordance with American College of Medical Genetics and Genomics.

Third, expanded carrier screening was studied. Due to a lack of inadequate information surrounding carrier frequencies in the Chinese population and small overlap of genes for screening by commercial panels, this dissertation screened a total of 1,543 ES and genome sequencing data from South Chinese for carrier status in over 315 genes. Consequently, among the 315 recessive genes, 358 variants (SNVs and small indels) and nine CNVs were classified as pathogenic or likely pathogenic. The data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.43% of the population) was a carrier for treatable inherited conditions..

This series of work demonstrates how the secondary use of NGS data after the initial diagnostic analysis can tackle three other important research questions that are pertinent to the implementation of genomic medicine. I explored the pharmacogenomics spectrum and cost burden, the burden of actionable incidental findings, and the potential for improvement in the optimization of commercially available ECS panels for the future of precision medicine. This groundwork can be utilize for better resource planning in the development of genomic medicine in Hong Kong.