Genetic and Phenotypic Variability in Chinese Patients With Branchio-Oto-Renal or Branchio-Oto Syndrome

Abstract

Background: Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities.Materials and Methods: Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning EYA1 and SIX1 alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes.Results: Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the EYA1 gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the SIX1 gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains.Conclusion: This is the first report of BOR/BOS caused by the SIX1 variant in China. Our findings increase the numbers of known EYA1 and SIX1 variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients.

Prenatal diagnosis and genetic analysis of a fetus with Branchio-oto-renal syndrome: A case report

“…There are several BOR cases reports in Chinese population, and only a total of 14 pathogenic/suspected pathogenic mutations of EYA1 in Chinese population have been recorded in database and literature. [21–25] In this study, the heterozygous mutation of EYA1: NM_000503.4: c.827-1G > C was first found in Chinese population. We identified the pathogenic gene associated with normal amniotic fluid and reduced fetal double kidney shape through trio-based whole exome sequencing, providing better prognostic advice for the fetus.…”

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

“…BOR/BO syndrome is clinically and genetically heterogeneous (3). The causative mutated genes include EYA1, SIX1, and SIX5, but no genetic cause has been identified in approximately 50% of cases (2)(3)(4). The genotypic spectrum of BOR/BO syndrome includes variants in EYA1 (40-75%), SIX1 (2%), and SIX5 (0-3.1%) (2,3).…”

“…Branchio-oto-renal (BOR) syndrome is characterized by branchial anomalies (branchial cleft or sinus, preauricular pits, or auricular deformity), hearing loss, and renal anomalies (1). The condition is rare and segregates in an autosomal-dominant manner (2). BOR syndrome is also termed branchio-otic (BO) syndrome if renal abnormalities are absent.…”

Ectomesenchymal Six1 controls mandibular skeleton formation

“…Six1 is widely expressed in craniofacial tissues of different origins, such as ectoderm, mesoderm, and endoderm ( Liu et al, 2019 ). SIX1 mutation causes human branchio-oto-renal syndrome (BOR), characterized by hearing loss, auricular deformities, residual branchial arches, and renal abnormalities ( Kumar et al, 2000 ; Ruf et al, 2004 ; Feng et al, 2021 ). However, the mechanisms by which SIX1 regulates craniofacial development, and skeletogenesis remain unclear.…”