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Introduction: Rapid advancements in Next Generation Sequencing (NGS) and bioinformatics tools have allowed physicians to obtain genetic testing results in a more rapid, cost-effective, and comprehensive manner than ever before. Around 50% of pediatric sensorineural hearing loss (SNHL) cases are due to a genetic etiology, thus physicians regularly utilize targeted sequencing panels that identify variants in genes related to SNHL. These panels allow for early detection of pathogenic variants which allows physicians to provide anticipatory guidance to families. Molecular testing does not always reveal a clear etiology due to the presence of multigenic variants with varying classifications, including the presence of Variants of Uncertain Significance (VUS). This study aims to perform a preliminary bioinformatics characterization of patients with variants associated with Type II Usher Syndrome in the presence of other multigenic variants. We also provide an interpretation algorithm for physicians reviewing molecular results with medical geneticists. Methods: Review of records for multigenic and/or VUS results identified several potential subjects of interest. For the purposes of this study, two ADGRV1 compound heterozygotes met inclusion criteria. Sequencing, data processing, and variant calling (the process by which variants are identified from sequence data) was performed at Invitae (San Francisco CA). The preliminary analysis followed the recommendations outlined by the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) in 2015 and 2019. The present study utilizes computational analysis, predictive data, and population data as well as clinical information from chart review and publicly available information in the ClinVar database. Results: Two subjects were identified as compound heterozygotes for variants in the gene ADGRV1. Subject 1's variants were predicted as deleterious, while Subject 2's variants were predicted as non-deleterious. These results were based on known information of the variants from ClinVar, multiple lines of computational data, population databases, as well as the clinical presentation. Discussion: Early molecular diagnosis through NGS is ideal, as families are then able to access a wide range of resources that will ultimately support the child as their condition progresses. We recommend that physicians build strong relationships with medical geneticists and carefully review their interpretation before making recommendations to families, particularly when addressing the VUS. Reclassification efforts of VUS are supported by studies like ours that provide evidence of pathogenic or benign effects of variants.
RESUMEN
PURPOSE: Pediatric cancer survivors often experience long-term adverse health conditions or late effects, including hearing loss, that are attributable to cancer therapy. Ototoxic late effects have been documented in patients with cancer treated with cisplatin-based chemotherapy and/or radiation. This study evaluated the late effects of methotrexate as compared to cisplatin and other cancer therapy agents on pediatric cancer survivors at the Children's Hospital of New Orleans in Louisiana (CHNOLA) and patients currently undergoing cancer treatment at Our Lady of the Lake (OLOL) Hospital in Baton Rouge, Louisiana. METHOD: A retrospective chart review was conducted of medical records from the CHNOLA Audiology Clinic and the Treatment After Cancer Late Effects clinic, which followed patients 2-19 years after cancer treatment completion and current patients with pediatric cancer at OLOL. This study identified pediatric cancer survivors between 2 and 24 years of age with treatment protocol information and audiological evaluations. Association studies were performed to calculate p values using an exact chi-square test. RESULTS: More than 44% of late-effects patients had significant hearing loss; mild-to-profound hearing loss was observed in 37.5% of patients who received methotrexate treatment without cisplatin or irradiation. Eighty-three percent of the patients who received cisplatin had late-effect hearing loss. In patients currently receiving cancer treatment, 12% had significant hearing loss. CONCLUSIONS: The results from this study suggest that children who receive therapies not clinically established as ototoxic (i.e., methotrexate) may still be at a high risk of developing long-term hearing loss as a late effect. Due to the high incidence rate of hearing loss among patients with pediatric cancer, we recommend that audiologists be part of the late-effects care team. This study also demonstrates that patients with pediatric cancer treated with methotrexate should receive routine long-term auditory monitoring as part of their standard of care to detect and manage hearing loss early, minimizing adverse outcomes.
