Objectives. We, herein, report two novel USH2A variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL).Methods. Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis.Results. We identified the following variants of USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G>A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as “uncertain significance” and “pathogenic,” respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant.Conclusion. Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.

Kim DK, et al. Allergy Asthma Immunol Res. 2020 Nov;12(6):980-993. https://doi.org/10.4168/aair.2020.12.6.980

Background: Obstructive sleep apnea (OSA) remains under-treated because continuous positive airway pressure, though efficacious, is frequently limited by poor tolerance and adherence. Long considered a purely anatomical disease refractory to drugs, OSA is now understood as the shared endpoint of four measurable endotypes—a collapsible upper airway, poor pharyngeal dilator-muscle responsiveness, high loop gain, and a low arousal threshold—each a distinct pharmacological target. This review synthesizes the mechanistic rationale and clinical evidence for targeting them. Methods: In this narrative review, we searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (January 2000 to February 2026) for randomized trials, meta-analyses, and mechanistic endotyping studies, appraising the evidence narratively. Results: Tirzepatide became the first drug approved for OSA, acting through weight loss to reduce obesity-related mechanical loading, and the noradrenergic–antimuscarinic combination AD109 met its primary endpoint in a pivotal phase 3 trial by targeting dilator-muscle activity independently of weight. Both, however, used AHI-based endpoints in clinically defined rather than endotype-selected populations; AD109’s placebo-corrected effect was modest (−4.0 events/h), and 21.2% versus 3.1% of participants discontinued for adverse events. They are therefore best described as mechanism-informed rather than endotype-validated. Carbonic anhydrase inhibition with acetazolamide or sultiame and selected sedating agents address ventilatory instability and a low arousal threshold, while solriamfetol and pitolisant relieve residual sleepiness. Conclusions: Mechanism-informed pharmacotherapy for OSA is now clinically credible, but scalable bedside endotyping, attention to tolerability, and trait-stratified trials are needed before treatment can be called endotype-guided.