A Genome-First Approach to Rare Variants in Dominant Postlingual Hearing Loss Genes in a Large Adult Population.

OBJECTIVE: To investigate the importance of rare variants in adult-onset hearing loss. STUDY DESIGN: Genomic association study. SETTING: Large biobank from tertiary care center. METHODS: We investigated rare variants (minor allele frequency <5%) in 42 autosomal dominant (DFNA) postlingual hearing loss (HL) genes in 16,657 unselected individuals in the Penn Medicine Biobank. We determined the prevalence of known pathogenic and predicted deleterious variants in subjects with audiometric-proven sensorineural hearing loss. We scanned across known postlingual DFNA HL genes to determine those most significantly contributing to the phenotype. We replicated findings in an independent cohort (UK Biobank). RESULTS: While rare individually, when considering the accumulation of variants in all postlingual DFNA genes, more than 90% of participants carried at least 1 rare variant. Rare variants predicted to be deleterious were enriched in adults with audiometric-proven hearing loss (pure-tone average >25 dB; P = .015). Patients with a rare predicted deleterious variant had an odds ratio of 1.27 for HL compared with genotypic controls (P = .029). Gene burden in DIABLO, PTPRQ, TJP2, and POU4F3 were independently associated with sensorineural hearing loss. CONCLUSION: Although prior reports have focused on common variants, we find that rare predicted deleterious variants in DFNA postlingual HL genes are enriched in patients with adult-onset HL in a large health care system population. We show the value of investigating rare variants to uncover hearing loss phenotypes related to implicated genes.

How Does the "Cookie-Bite" Audiogram Shape Perform in Discriminating Genetic Hearing Loss in Adults?

"Cookie-bite" or U-shaped audiograms-specifically, those showing midfrequency sensorineural hearing loss (HL)-are traditionally taught to be associated with genetic HL; however, their utility as a screening tool has not been reported. We aim to determine the performance of a cookie-bite audiogram shape in stratifying patients carrying putative loss-of-function variants in known HL genes from wild-type controls. We merged audiometric and exome sequencing data from adults enrolled in a large biobank at a tertiary care center. Of 321 patients, 50 carried a putative loss-of-function variant in an HL gene. The cookie-bite shape was present in 9 of those patients, resulting in low sensitivity (18%) and positive predictive value (15%) in stratifying genetic carrier status; 84% of patients with a cookie-bite audiogram did not carry a genetic variant. A cookie-bite audiogram should not be used to screen adults for possible genetic testing.

Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults.

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.

New Age Mentoring and Disruptive Innovation-Navigating the Uncharted With Vision, Purpose, and Equity.

For individuals aspiring to a career in otolaryngology-head and neck surgery, mentorship can shape destiny. Mentorship helps assure safe passage into the specialty, and it influences the arc of professional development across the career continuum. Even before the novel coronavirus disease 2019 (COVID-19) pandemic, technology and social networking were transforming mentorship in otolaryngology. Now, in an increasingly virtual world, where in-person interactions are the exception, mentorship plays an even more pivotal role. Mentors serve as trusted guides, helping learners navigate accelerating trends toward early specialization, competency-based assessments, and key milestones. However, several structural barriers render the playing field unlevel. For medical students, cancellation of visiting clerkships, in-person rotations, and other face-to-face interactions may limit access to mentors. The pandemic and virtual landscape particularly threaten the already-leaky pipeline for underrepresented medical students. These challenges may persist into residency and later career stages, where structural inequities continue to subtly influence opportunities and pairings of mentors and mentees. Hence, overreliance on serendipitous encounters can exacerbate disparities, even amid societal mandates for equity. The decision to take deliberate steps toward mentoring outreach and engagement has profound implications for what otolaryngology will look like in years to come. This article introduces the concept of new age mentoring, shining a light on how to modernize practices. The key shifts are from passive to active engagement; from amorphous to structured relationships; and from hierarchical dynamics to bidirectional mentoring. Success is predicated on intentional outreach and purposefulness in championing diversity, equity, and inclusion in the progressively technology-driven landscape.

OHNS Residency Program and Applicant Social Media Presence During the COVID-19 Pandemic.

OBJECTIVES: In addition to clinical and social disruption, the Coronavirus Disease 2019 (COVID-19) pandemic has affected many aspects of the otolaryngology residency application process. With delays in the 2021 Electronic Residency Applications Service (ERAS) timeline, students and programs have had more time to interact prior to the formal application process. This communication will report recent trends in social media presence by OHNS residency programs, and discuss mechanisms to compensate for decreased applicant-program interactions using social media ahead of the 2021 Match. METHODS: In a cross-sectional study of the accredited otolaryngology residency programs in the United States, the number of social media profiles on Twitter, Instagram, and Facebook from 2009 to 2019 were recorded and compared. RESULTS: Most programs (61%) have at least 1 social media profile. Over the past 10 years, the number of programs on social media has increased. During the COVID-19 pandemic, Twitter and Instagram showed higher rates of growth compared to Facebook. With the reduction of in-person opportunities for interactions, both applicants and programs are utilizing social media to showcase their values and their research. Twitter, in particular, also serves as a platform for professional networking. CONCLUSION: Both Twitter and Instagram are growing in popularity among programs and applicants to enhance networking. Social media is a powerful tool for networking and may help compensate for limitations imposed on the residency match process by the COVID-19 pandemic while maintaining professionalism considerations. The impact of social media on the 2021 otolaryngology residency match is an evolving phenomenon.

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.

Genetics of Postlingual Sensorineural Hearing Loss.

Literature and clinical practice around adult-onset hearing loss (HL) has traditionally focused on environmental risk factors, including noise exposure, ototoxic drug exposure, and cardiovascular disease. The most common diagnosis in adult-onset HL is presbycusis. However, the age of onset of presbycusis varies, and patients often describe family history of HL as well as individual variation in progression and severity. In recent years, there has been accumulating evidence of gene-environment interactions underlying adult cases of HL. Susceptibility loci for age-related HL have been identified, and genes related to postlingual nonsyndromic HL continue to be discovered through individual reports and genome-wide association studies. This review will outline main concepts in genetics as related to HL, identify implicated genes, and discuss clinical implications. Laryngoscope, 131:401-409, 2021.

A Multimodal Multi-institutional Solution to Remote Medical Student Education for Otolaryngology During COVID-19.

During the coronavirus 2019 pandemic, there has been a surge in production of remote learning materials for continued otolaryngology resident education. Medical students traditionally rely on elective and away subinternship experiences for exposure to the specialty. Delays and cancellation of clinical rotations have forced medical students to pursue opportunities outside of the traditional learning paradigm. In this commentary, we discuss the multi-institutional development of a robust syllabus for medical students using a multimodal collection of resources. Medical students collaborated with faculty and residents from 2 major academic centers to identify essential otolaryngology topics. High-quality, publicly available, and open-access content from multiple sources were incorporated into a curriculum that appeals to a variety of learners. Multimodal remote education strategies can be used as a foundation for further innovation aimed at developing tomorrow's otolaryngologists.

Hemodialysis-induced cardiovascular disease.

More than half of all deaths among end stage renal disease (ESRD) patients are due to cardiovascular disease (CVD). Cardiovascular changes secondary to renal dysfunction, including fluid overload, uremic cardiomyopathy, secondary hyperparathyroidism, anemia, altered lipid metabolism, and accumulation of gut microbiota-derived uremic toxins like trimethylamine N-oxidase, contribute to the high risk for CVD in the ESRD population. In addition, conventional hemodialysis (HD) itself poses myocardial stress and injury on the already compromised cardiovascular system in uremic patients. This review will provide an overview of cardiovascular changes in chronic kidney disease and ESRD, a description of reported mechanisms for HD-induced myocardial injury, comparison of HD with other treatment modalities in the context of CVD, and possible management strategies.

Gut microbiome and its role in cardiovascular diseases.

PURPOSE OF REVIEW: In recent years, an interest in intestinal microbiota-host interactions has increased due to many findings about the impact of gut bacteria on human health and disease. Dysbiosis, a change in the composition of the gut microbiota, has been associated with much pathology, including cardiovascular diseases (CVD). This article will review normal functions of the gut microbiome, its link to CVD, and potential therapeutic interventions. RECENT FINDINGS: The recently discovered contribution of gut microbiota-derived molecules in the development of heart disease and its risk factors has significantly increased attention towards the connection between our gut and heart. The gut microbiome is virtually an endocrine organ, arguably the largest, capable of contributing to and reacting to circulating signaling molecules within the host. Gut microbiota-host interactions occur through many pathways, including trimethylamine-N-oxide and short-chain fatty acids. These molecules and others have been linked to much pathology including chronic kidney disease, atherosclerosis, and hypertension. SUMMARY: Although our understanding of gut microbiota-host interactions has increased recently; many questions remain about the mechanistic links between the gut microbiome and CVD. With further research, we may one day be able to add gut microbiota profiles as an assessable risk factor for CVD and target therapies towards the gut microbiota.