Molecular Findings Among Patients for Whole Exome Sequencing and mitochondrial genome assessment

Abstract

Objective: Whole exome sequencing (WES) is increasingly used as a diagnostic tool in medicine. We report the diagnostic yield of WES and mitochondrial genome in 2226 consecutive cases at a single clinical laboratory. Methods: We performed a retrospective analysis of consecutive WES reports of 2226 patients affected by a range of genetic disorders. The WES was performed solely for the probands and in a higher diagnostic capacity. We determined the diagnostic rate of WES overall as well as by phenotypic category, mode of inheritance, mitochondrial genome variant, and copy number variants (CNVs). Results: Of 2226 individuals having diagnostic WES proband-only, the overall diagnostic yield of WES was 34.59%. autosomal dominant (45.58%), followed by autosomal recessive (31.95%), X-linked (9.61%), and mitochondrial (0.65%), The remaining diagnoses were based on a total of 94 copy number variants (12.21%) reported from WES data. The CNV variation in children accounted for 67.02% of the total CNV variation. Molecular diagnoses were reported for 31.14% (373/1198) of adults, lower than a primarily pediatric population (38.62%, 397/1028). A While the majority of molecular diagnoses were related to nuclear genes, mitochondrial genome sequencing included in the WES test yielded five diagnoses, and all confirmed mitochondrial diseases were detected in adults. The highest positivity rate was observed in children aged 1-4 years old (43.72%, 80/183). Patients with integument system disorders had the highest diagnostic yield (58.33%, 59/151). The endocrine and metabolic disorders were the most common systems in both adults and children (261, 217). However, in adults, the highest diagnosis rate was for integument system disorders (71.43%, 30/42), while in children, the highest diagnosis rate was for disorders involving hearing (61.73%, 50/81). In addition to cases with a definitive diagnosis, in 8.4% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis. Conclusions: WES proband-only provided a definitive molecular diagnosis for 34.59% of a large cohort of patients referred for evaluation for evaluation of suspected genetic conditions, that analysis of WES simultaneously analyze the SNVs, Exons, mitochondrial genome and CNVs significantly improves the diagnostic yield compared with WES single detection method, and facilitates identification of novel candidate genes. The yield of whole exome sequencing in this study may have advantages over reported molecular diagnostic methods.