Molecular Genetic Etiology and Revisiting the Middle Ear Surgery Outcomes of Branchio-Oto-Renal Syndrome: Experience in a Tertiary Referral Center

Abstract

ObjectivesTo explore the phenotypes and genotypes of patients with branchio-oto-renal (BOR) and branchio-otic (BO) syndrome, and to analyze the middle ear surgery outcomes qualitatively and quantitatively, proposing a factor usefully prognostic of surgical outcomes.Study designRetrospective cohort study.SettingTertiary referral center.PatientsEighteen patients with BOR/BO syndrome in 12 unrelated Korean families.InterventionMiddle ear surgery, including either stapes surgery or ossicular reconstruction.Main Outcome MeasureClinical phenotypes, genotypes, and middle ear surgery outcomesResultsEight probands (66.7%) were confirmed genetically; the condition segregated as a dominant or de novo trait. Six EYA1 heterozygous variants were identified by exome sequencing and multiplex ligation-dependent probe amplification. All variants were pathogenic or likely pathogenic based on the ACMG/AMP guidelines. Two novel EYA1 frameshift variants (p.His373Phefs*4 and p.Gln543Asnfs*90) truncating a highly conserved C-terminal Eya domain were identified, expanding the genotypic spectrum of EYA1 in BOR/BO syndrome. Remarkably, middle ear surgery was individualized to ensure optimal audiological outcomes and afforded significant audiological improvements, especially in BOR/BO patients without enlarged vestibular aqueducts (EVAs). A significant difference in air-bone gap closure after middle ear surgery was noted between the two groups even after adjusting for confounders: −20.5 dB in ears without EVAs (improvement) but 0.8 dB in ears with EVAs (no change or deterioration). Furthermore, the success rate was significantly associated with the absence of EVA.ConclusionsThe results of this study were against the notion that middle ear surgery is always contraindicated in patients with BOR/BO syndrome, and an EVA could be a negative prognostic indicator of middle ear surgery in BOR/BO patients. This may aid to determine the strategy of audiological rehabilitation in patients with BOR/BO syndrome.

CRISPR-based editing strategies to rectifyEYA1complex genomic rearrangement linked to haploinsufficiency

“…In conclusion, our results pave the way for the potential development of gene editing therapeutics for the clinical application of human genetic disorders caused by pathogenic SVs such as inversion and genomic rearrangements. In particular, BOR/BO syndrome stands as a representative case where hearing impairment is the most penetrant symptom 17,45 . Most branchial anomalies associated with this syndrome can be managed surgically, and the renal phenotype is rare.…”

A Novel <i>EYA1</i> Mutation Causing Alternative RNA Splicing in a Chinese Family With Branchio-Oto Syndrome: Implications for Molecular Diagnosis and Clinical Application

“…Etiologically, the EVA is considered a pathological third window that prevents adequate energy delivery in the inner ear, even if the middle ear is properly reconstructed. In view of the latest research, Nam et al [ 70 ] proposed that the presence of EVA in patients with BOS/BORS might be a negative indicator of poor prognosis for middle ear surgery. Although the currently available studies suggest a correlation between the presence or absence of EVA and the success rate of auditory improvement, this inference is limited by the small sample size of these studies and thus merits further exploration.…”

Phenotypic and molecular basis of SIX1 variants linked to non-syndromic deafness and atypical branchio-otic syndrome in South Korea

“…Consequently, we identified five unrelated Korean families (approximately 50%) with segregating as a dominant trait. To further elaborate the clinical phenotypes of SIX1 variants, our study included 15 more Korean families (encompassing 16 affected individuals) who possessed causative EYA1 variants linked to BOR/BO syndrome from the in-house database 24 . These additions enabled a comparative analysis of the phenotypic manifestations between individuals with SIX1 and EYA1 variants.…”