Branchio-oto-renal (BOR) syndrome is characterized by branchiogenic malformation, hearing loss, and renal anomalies, with EYA1, SIX1, and SIX5 known as the causative genes. As BOR syndrome presents with various clinical phenotypes, its characteristics and genotype-phenotype correlations remain unknown. In this study, we aimed to clarify the detailed hearing loss phenotypes and genotype-phenotype correlations of BOR syndrome. In this study, we performed an etiological analysis of 169 BOR syndrome patients from 129 families. We also performed genetic testing for 78 probands. In all, 66.7% of BOR patients carried EYA1 variants, whereas 17.9% carried SIX1 variants. We also clarified the detailed clinical features including the prevalence of major and minor symptoms, asymmetrical hearing loss, type of hearing loss, severity of hearing loss and detailed clinical characteristics of auricular, external ear, and middle ear and inner ear anomalies. In terms of genotype-phenotype correlations, patients with SIX1 variants had no kidney anomalies and fewer middle ear anomalies. We clarified the detailed hearing loss phenotypes of BOR syndrome patients. Our study results will contribute to a better understanding and clinical management of BOR syndrome patients.

The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.

Branchio-Oto-Renal (BOR) syndrome is a multisystemic autosomal dominant disorder characterized by pre-auricular pits, hearing loss, branchial fistulae, and renal urinary tract malformations. Although renal involvement is common in BOR syndrome, studies on its renal pathological features remain relatively scarce. An 18-year-old male presented with proteinuria, renal insufficiency, hearing loss, preauricular fistulas, and branchial fistulas. Imaging revealed small kidneys, and renal biopsy showed mild mesangial proliferative glomerular lesions, mild chronic tubulointerstitial injury with acute exacerbation. Electron microscopy demonstrated focal thinning of the glomerular basement membrane and segmental foot process effacement. Genetic testing identified a pathogenic variant (EYA1 c.1081 C > T p.Arg361*). The clinical manifestations and severity of BOR syndrome are highly variable, making it prone to misdiagnosis or missed diagnosis. Genetic testing identified the pathogenic EYA1 variant in this case, and the pathological feature of focal thinning of the glomerular basement membrane was reported for the first time. This expanded the understanding of renal damage associated with this disease. For patients with unexplained renal insufficiency, detailed physical examination combined with genetic testing is necessary to improve the early diagnosis rate of BOR syndrome. The online version contains supplementary material available at 10.1186/s12882-025-04635-w.

Branchio-oto-renal (BOR) syndrome is an uncommon disorder inherited in an autosomal dominant manner. Its main clinical manifestations include branchial cleft cysts, anterior auricular fistula, hearing impairment, and kidney malformations. BOR syndrome is associated with heterozygous pathogenic variants including EYA1, SIX1, and SIX5. The study focused on a 13-year-old Chinese boy who presented with hearing impairment, renal malformations, and bony atresia of the right external auditory canal with microtia. The boy's clinical manifestations met the diagnostic criteria for BOR syndrome. Two of the boy's family members underwent clinical examination. However, neither displayed a phenotype associated with BOR syndrome. The boy and his two relatives provided blood samples for genomic DNA extraction, followed by Sanger sequencing. A novel mutation in the GREB1L gene was identified in the boy, but neither of his family members exhibited the same variant. Identifying a novel mutation in GREB1L offers valuable insights into the genotype-phenotype correlation of BOR syndrome, improving the precision of early diagnosis and promoting the advancement of personalized treatment strategies.

A distinct form of cochlear hypoplasia, characterized by the preservation of the first half of the basal turn with hypoplastic and anteriorly displaced upper turns, was historically associated with branchio-oto-renal (BOR) syndrome, but can also occur in other genetic, syndromic and non-syndromic causes of hearing loss. This study aims to describe this phenotype with relative preservation of the basal turn, particularly its first half, in a significant proportion of cochlear hypoplasia cases due to different causes. We retrospectively reviewed temporal bone imaging from 125 patients (250 ears) with cochlear malformations from a tertiary pediatric center, focusing on cases where the basal turn was partially or completely preserved. Temporal bone CT and internal auditory meatus MRI were assessed for cochlear morphology and associated anomalies and genetic, clinical and syndromic associations described. Fifty-eight patients exhibited a preserved basal turn with different degrees of hypoplasia of the upper turns. These cases were grouped into five etiological clusters: branchio-oto-renal (BOR), CHARGE, Walker-Warburg (WWS) syndromes, other genetic cases and likely non-genetic cases (including syndromic conditions without a genetic cause identified such as oculo-auriculo-vertebral spectrum - OAVS). Genetic cases may show bilateral and symmetrical appearances, aberrant facial nerve courses were observed in 30 patients. Preservation of the first half of the basal turn suggests developmental arrest between 50 and 54 days of gestation, and is common across genetic and non-genetic conditions of cochlear hypoplasia. Frequent facial nerve anomalies may complicate cochlear implantation. Integrating imaging with embryological insights supports the need for refined, developmentally-based classification systems.