Lessons learned from rapid exome sequencing for 575 critically ill patients across the broad spectrum of rare disease

Abstract

Introduction: Rapid exome sequencing (rES) has become the first-choice genetic test for critically ill patients, mostly neonates, young infants, or fetuses in prenatal care, in time-sensitive situations and when it is expected that the genetic test result may guide clinical decision making. The implementation of rES has revolutionized medicine by enabling timely identification of genetic causes for various rare diseases. The utilization of rES has increasingly been recognized as an essential diagnostic tool for the identification of complex and undiagnosed genetic disorders. Methods: We conducted a retrospective evaluation of our experiences with rES performed on 575 critically ill patients from various age groups (prenatal to adulthood), over a four-year period (2016-2019). These patients presented with a wide spectrum of rare diseases, including but not limited to neurological disorders, severe combined immune deficiency, and cancer. Results: During the study period, there was a significant increase in rES referrals, with a rise from a total of two referrals in Q1-2016 to 10 referrals per week in Q4-2019. The median turnaround time (TAT) decreased from 17 to 11 days in the period 2016-2019, with an overall median TAT of 11 days (IQR 8-15 days). The overall diagnostic yield for this cohort was 30.4%, and did not significantly differ between the different age groups (e.g. adults 22.2% vs children 31.0%; p-value 0.35). However, variability in yield was observed between clinical entities: craniofacial anomalies yielded 58.3%, while for three clinical entities (severe combined immune deficiency, aneurysm, and hypogonadotropic hypogonadism) no diagnoses were obtained. Discussion: Importantly, whereas clinical significance is often only attributed to a conclusive diagnosis, we also observed impact on clinical decision-making for individuals in whom no genetic diagnosis was established. Hence, our experience shows that rES has an important role for patients of all ages and across the broad spectrum of rare diseases to impact clinical outcomes.

Keywords: clinical outcome; diagnostic workflow; diagnostic yield; rapid exome sequencing; turnaround time.

FIGURE 1

Overview of cohort categorized by diagnostic strategies and age groups (A) Diagnostic strategies were classified into four categories: i) specific phenotypic presentation requiring the analysis of a single disease-gene panel, applied to 15% of patients; ii) clinical spectrum requiring the analysis of multiple disease-gene panels (33% of patients); iii) Mendeliome analysis with a specific emphasis on certain disease categories (20%), and iv) Mendeliome without a clear disease focus because of too non-specific and/or too broad phenotypic presentation (32%). (B) Distribution of diagnostic strategies across the different age groups. (C) Total number of requested gene panels and their distribution across different age groups.

FIGURE 2

Overview of rES diagnostic yield categorized by diagnostic strategies and age groups (A) Pie chart showing the overall percentage of diagnostic yield obtained in 575 patients. (B) Diagnostic success rates across diagnostic strategies, (C) age groups and (D) disease gene panels.