The genetic etiology of hearing loss (HL) in Ecuador remains largely unexplored. This study investigates the spectrum of genetic variants associated with HL in a cohort of 66 Ecuadorian families using Exome or Genome sequencing (ES/GS). We identified pathogenic and likely pathogenic variants underlying HL in 27 families (41

IntroductionOculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant disorder caused by pathogenic BCOR variants and characterized by congenital cataracts, microcornea, and secondary glaucoma. Multilocus pathogenic variation (MPV), in which independent variants contribute to disease burden, can further complicate syndromic presentations and alter surgical planning. This case highlights the importance of longitudinal genetic evaluation in complex ophthalmic disease.MethodsComprehensive ophthalmic evaluation, multimodal imaging, and systemic assessment were performed. Trio exome sequencing was used as part of the genetic diagnostic work-up. Standard preoperative cardiovascular imaging was completed before planned glaucoma surgery.ResultsA 15-year-old female with OFCD exhibited congenital cataracts, bilateral microcornea, and persistent secondary glaucoma requiring multiple interventions. Trio exome sequencing confirmed a de novo pathogenic BCOR mutation and identified a paternally inherited pathogenic MYLK variant associated with thoracic aortic aneurysm and dissection. Although initially cleared for glaucoma surgery, routine preoperative screening revealed progressive ascending aortic dilation linked to the MYLKM variant, leading to postponement of ocular surgery due to increased anesthetic risk.DiscussionThis case demonstrates how MPV can significantly influence ophthalmic surgical decision-making. Genetic findings initially considered secondary became critical as cardiovascular risk evolved. Multidisciplinary coordination between ophthalmology and genetics is essential to integrate evolving genomic insights into perioperative care and ensure optimal patient safety.

Bilateral administration of human OTOF gene therapy appears safe, and preliminary data suggest that it could effectively treat a rare form of hereditary hearing loss by enhancing speech perception, sound source localization and overall auditory experience.

Hearing loss (HL) is a common sensory impairment that affects approximately 50% of the population in their lifetime. With more than half of congenital or early childhood-onset sensorineural HL attributed to genetic factors, advances in genetic testing have allowed etiologic diagnosis, leading to improved genetic counseling and potential treatments. Thirty percent of patients with HL present additional syndromic findings. In addition to well-known forms of syndromic HL, such as Usher, branchio-oto-renal, and Waardenburg syndromes, there are over 400 rare syndromes that can include HL as a finding.

Rare diseases affect 6%-8% of the population and present diagnostic challenges, particularly for historically marginalized ethnic and racial groups. The Undiagnosed Diseases Network (UDN) aims to enhance diagnosis rates and research participation among such minoritized groups. A retrospective review was conducted from 2015 to 2023, analyzing 2235 UDN participants to evaluate its progress toward this objective. Data on demographics, disease phenotypes, diagnostic outcomes, and socioeconomic factors were collected and statistical analyses assessed differences among ethnic and racial groups. This demonstrated that Hispanic and Black non-Hispanic groups were underrepresented, while White non-Hispanic participants were overrepresented in the UDN compared to the US population. Individuals whose primary language was not English were also significantly underrepresented. Diagnosis rates varied, with the highest rates among Asian non-Hispanic (39.5%) and Hispanic (35.3%) groups and the lowest rate in the White non-Hispanic group (26.8%) (p < 0.001). Binomial logistic regression found, however, that only participant age and disease phenotype predicted the likelihood of receiving a diagnosis (p < 0.001). Persistent ethnic and racial disparities in UDN participation appear to be associated with major differences in application rates. Under-enrollment of historically marginalized ethnic and racial groups may be due to economic hardships and language barriers. No differences in the diagnostic yield among ethnic and racial groups were observed after controlling for other factors. This work highlights the value of comprehensive genetic evaluations for addressing healthcare disparities and suggests priorities for advancing inclusion in rare disease research.

BACKGROUND:We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS:The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION:This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.