A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

Abstract

Exome sequencing (ES) has become one of the important diagnostic tools in clinical genetics with a reported diagnostic rate of 25-58%. Many studies have illustrated the diagnostic and immediate clinical impact of ES. However, up to 75% of individuals remain undiagnosed and there is scarce evidence supporting clinical utility beyond a follow-up period of >1 year. This is a 3-year follow-up analysis to our previous publication by Mak et al. (NPJ Genom. Med. 3:19, 2018), to evaluate the long-term clinical utility of ES and the diagnostic potential of exome reanalysis. The diagnostic yield of the initial study was 41% (43/104). Exome reanalysis in 46 undiagnosed individuals has achieved 12 new diagnoses. The additional yield compared with the initial analysis was at least 12% (increased from 41% to at least 53%). After a median follow-up period of 3.4 years, change in clinical management was observed in 72.2% of the individuals (26/36), leading to positive change in clinical outcome in four individuals (11%). There was a minimum healthcare cost saving of HKD$152,078 (USD$19,497; €17,282) annually for these four individuals. There were a total of six pregnancies from five families within the period. Prenatal diagnosis was performed in four pregnancies; one fetus was affected and resulted in termination. None of the parents underwent preimplantation genetic diagnosis. This 3-year follow-up study demonstrated the long-term clinical utility of ES at individual, familial and health system level, and the promising diagnostic potential of subsequent reanalysis. This highlights the benefits of implementing ES and regular reanalysis in the clinical setting.

Keywords: Clinical genetics; Genetics research; Outcomes research; Paediatrics.

Fig. 1. The pregnancy outcomes of five families who sought advice in assisted reproductive service within the study’s follow-up period (median of 3.4 years).

PND prenatal diagnosis, TOP termination of pregnancy; *: ongoing twin pregnancy at the time of genetic diagnosis.

Fig. 2. The diagnostic yield of exome sequencing initial analysis and reanalysis from published studies and our current study.

We searched PubMed with the search terms “exome” and “reanalysis” to identify relevant studies. There were no language and date restrictions. Only studies that provide both the initial analysis and reanalysis data were included. *Liu et al. cohort 1 and Liu et al. cohort 2 are two separate patient cohorts from the same reanalysis study with different approach and time frame (cohort 1: manual reanalysis over a 5-year period; cohort 2: semiautomated reanalysis over a 4-year period).