Each year, more than 12,000 babies are born with hearing loss in the US alone, and about half of them are due to genetic causes. Knowing the exact genetic lesions allows early diagnosis even before the onset of noticeable symptoms, informs the choice of optimal management plans, and predicts risks for relatives including future babies. In light of promising advances in gene therapy, it will soon become essential to identify the causative genetic lesion so that personalized therapy can specifically target the culprit lesio to maximize efficacy while minimize side-effects. Therefore, the overall goal of this project is to develop accurate and sensitive clinical molecular diagnostic tests to improve care for patients with hearing loss. Targeted high-throughput sequencing of genomic DNA has become state of the art in clinical molecular genetic diagnostics, resulting in the identification of a large numbe of DNA variants. However, the diagnostic yield remains unsatisfactory due to the lack of functional and statistical evidence to determine their clinical significance. This proposal aims to develop OtoScript, a fundamentally different genetic testing platform based on high-throughput sequencing of messenger RNA instead of genomic DNA. The hypothesis is that OtoScript will not only identify genetic variation that may be missed by conventional genomic sequencing, but will also reveal functional consequences at the transcriptional level, allowing accurate assessment of clinical significance. Furthermore, this project will provide a resource for the auditory research community to study the molecular basis of hearing loss.
In Aim 1, the feasibility and validity of OtoScript to identify genetic variations in hearing loss genes will be evaluated. OtoScript performance metrics will be compared to the current standard of care, specifically the clinically validated OtoGenome test in a CLIA-certified clinical laboratory. In Ai 2, the capability of OtoScript to enhance interpretation of genetic testing results will be assesse in four functional aspects at the transcriptional level: levels of gene expression, the number of affected homologous chromosomes, aberrant transcripts, and RNA-editing. In addition, new findings from this study will be disseminated to the research community via the Shared Harvard Inner Ear Laboratory Database (SHIELD, https://shield.hms.harvard.edu/). This novel approach holds the potential to improve the accuracy and efficiency of clinical molecular genetic diagnosis of hearing loss.
Clinical molecular genetic diagnosis informs medical management for patients and their family members. This study aims to develop a new high-throughput platform to increase the diagnostic yield of genetic testing and to shed light on the molecular mechanism of hearing loss. This will in turn improve patient care, and ultimately lead to novel strategies to treat and prevent hearing loss.