Reanalysis of exome sequencing data in ۲۰ negative hearing loss samples: efficiencies and benefits

Backgrounds: Hearing loss is the most common sensory defect that affects ~ ۱/۵۰۰newborns and over ۶% of the population worldwide. Approximately ۵۰–۶۰% of hearing losspatients are attributed to genetic causes. With the advancement of Next-Generation Sequencingand bioinformatics tools, exome sequencing (ES) has recently become the most efficientdiagnostic test for patients with hearing loss. According to various studies, up to ۵۰% of patientsare still undiagnosed; so re-analysis of ES data may improve diagnostic rates in patients who donot have an initial molecular diagnosis.Materials and Methods: The exome and phenotypic data of twenty undiagnosed hearing lossIranian patients were re-examined and re-analyzed. ES reanalysis was performed utilizing themost recent GATK and other improved bioinformatics tools to improve variant identification andannotation. The GATK GermlineCNand VCaller was used to perform ES-based CNV analysis.Results: We found two pathogen variants in the DIAPH۱ and FGF۳ genes in two families afterre-evaluating clinical and ES data. These causal variants were not detected in initial ES analysis.The new finding in DIAPH۱ was determined to be due to initially incomplete phenotypicinformation. A frameshift variation was found in FGF۳ which was missed probably because ofmapping error for indels in early versions of analytical pipeline. This is the first reported case inIranian population with mutation in FGF۳ gene. Also, more clinical evaluations are underway.Conclusion: Our preliminary analysis resulted in more than ۱۰% increase in diagnostic yield,indicating that periodical reanalysis should be performed in clinical practice.

کلیدواژه ها:

Reanalysis ، Whole exome sequencing ، Hearing loss ، Diagnostic yield