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.
Highlights
Branchio-oto-renal syndrome-1 (BOR1; OMIM#113650), known as Melnick–Fraser syndrome, is a rare autosomal dominant affected family members disease with an incidence of approximately one in 40,000; it affects 2% of profoundly deaf children (Melnick et al, 1975; Fraser et al, 1980)
Five individuals clinically diagnosed with BOR or branchio-oto syndrome (BOS) were recruited at the Affiliated Hospital of Zhengzhou University
We identified nine patients from five families with BOR or BOS, using the criteria established by Chang et al (2004)
Summary
Branchio-oto-renal syndrome-1 (BOR1; OMIM#113650), known as Melnick–Fraser syndrome, is a rare autosomal dominant affected family members disease with an incidence of approximately one in 40,000; it affects 2% of profoundly deaf children (Melnick et al, 1975; Fraser et al, 1980). The SIX1 gene, known as sine oculis homeobox homolog 1, encodes a transcription factor (Six1) that functions as a DNA-binding protein in combination with Eya, leading to 3.0–4.5% of BOR/BOS cases (Ruf et al, 2004; Wang et al, 2018). Eya does not have direct DNA-binding ability Instead, it functions as a transcription co-activator and interacts with Six, providing a molecular mechanism for activation of specific target genes that modulate precursor cell proliferation, survival, and differentiation during multiple types of organogenesis (Li et al, 2003; Ruf et al, 2004). 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. We characterized the clinical features and genetic etiology of BOR/ BOS in several Chinese families and explored the genotypes and phenotypes of BOR/ BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities
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