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.

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

“…The discovery of gene‐disease and variant‐disease associations is continually growing necessitating regular reevaluation of unsolved exomes 48,49 . In line with previous studies demonstrating an improved diagnostic yield by systematic reanalysis of existing data, 48,50 we achieved a definitive diagnosis in two additional individuals (among 80 reanalyzed individuals with initial negative results). Beyond, reanalysis in our cohort lead to the identification of two novel candidate genes for NDDs highlighting the potential of subsequent reanalysis also for disease gene discovery 41,51 …”

Clinical Exome Reanalysis: Current Practice and Beyond

“…For the last category, it is expected that exome reanalysis would increase diagnostic yield. Based on previously published studies, exome reanalysis results in an increase in diagnostic yield of approximately 12%, with reported increases ranging from 5 to 26% [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Although the reported interval between initial analysis and reanalysis varies from 6 months to 7 years among reanalysis studies, the majority of reanalyses were performed at 1-to 2-year intervals [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Ultimately, such efforts may result in changes to the clinical management of the patients and families. Several previous studies have demonstrated the clinical validity of exome reanalysis to increase the diagnostic yield [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and the American College of Medical Genetics and Genomics (ACMG) recently published a series of points to consider regarding the reevaluation and reanalysis of genomic test results at various levels [20]. While challenges remain, it is important for both ordering physicians and clinical laboratories to recognize the need for exome reanalysis as a routine clinical practice, given the evolving nature of the genomic field.…”

The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

“…For example, Fogel et al (2014) reported a success rate of 73% (22/30) in diagnosing patients with sporadic cerebellar ataxia. Reanalysis of the undiagnosed exomes and coupling WES with other genetic approaches, such as mRNA sequencing and CNV detection, also increase WES’s diagnostic yield ( Deelen et al, 2019 ; Jalkh et al, 2019 ; Fung et al, 2020 ; Matalonga et al, 2020 ). CNVs are common in some SCD subtypes, e.g., SPG4 (OMIM # 182601) and SCA15 (OMIM # 606658; Depienne et al, 2007 ; Hsiao et al, 2017 ).…”

“…One study reported a rise of 7% in the diagnostic success rate upon reanalyzing the WES data of a cohort of SCD patients ( Ngo et al, 2020 ). Recent reports advocate for a periodic reanalysis of WES data ( Jalkh et al, 2019 ; Liu et al, 2019 ; Fung et al, 2020 ; Ngo et al, 2020 ). The 5-year cumulative increase in the diagnostic success rate upon WES data reanalysis ranges from 12 to 22% ( Liu et al, 2019 ).…”