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Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome.

ABSTRACT: Some patients have an atypical form of branchio-oto-renal (BOR) syndrome, which does not satisfy the diagnostic criteria, despite carrying a pathogenic variant (P variant) or a likely pathogenic variant (LP variant) of a causative gene. P/LP variants phenotypic indices have yet to be determined in patients with typical and atypical BOR syndrome. We hypothesized that determining phenotypic and genetic differences between patients with typical and atypical BOR syndrome could inform such indices. Subjects were selected from among patients who underwent genetic testing to identify the cause of hearing loss. Patients were considered atypical when they had two major BOR diagnostic criteria, or two major criteria and one minor criterion; 22 typical and 16 atypical patients from 35 families were included. Genetic analysis of EYA1, SIX1, and SIX5 was conducted by direct sequencing and multiplex ligation-dependent probe amplification. EYA1 P/LP variants were detected in 25% and 86% of atypical and typical patients, respectively. Four EYA1 P/LP variants were novel. Branchial anomaly, inner ear anomaly, and mixed hearing loss were correlated with P/LP variants. Development of refined diagnostic criteria and phenotypic indices for atypical BOR syndrome will assist in effective detection of patients with P/LP variants among those with suspected BOR syndrome.

SUBMITTER: Masuda M

PROVIDER: S-EPMC8770796 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

| S-EPMC8634836 | biostudies-literature

Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.

Project description:Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.

| S-EPMC1852719 | biostudies-literature

Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations.

Project description:Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by hearing loss, branchial arch defects, and renal anomalies. Recently, eight mutations in the SIX1 homeobox gene were discovered in BOR patients. To characterize the effect of SIX1 BOR mutations on the EYA-SIX1-DNA complex, we expressed and purified six of the eight mutants in Escherichia coli. We demonstrate that only the most N-terminal mutation in SIX1 (V17E) completely abolishes SIX1-EYA complex formation, whereas all of the other mutants are able to form a stable complex with EYA. We further show that only the V17E mutant fails to localize EYA to the nucleus and cannot be stabilized by EYA in the cell. The remaining five SIX1 mutants are instead all deficient in DNA binding. In contrast, V17E alone has a DNA binding affinity similar to that of wild type SIX1 in complex with the EYA co-factor. Finally, we show that all SIX1 BOR mutants are defective in transcriptional activation using luciferase reporter assays. Taken together, our experiments demonstrate that the SIX1 BOR mutations contribute to the pathology of the disease through at least two different mechanisms that involve: 1) abolishing the formation of the SIX1-EYA complex or 2) diminishing the ability of SIX1 to bind DNA. Furthermore, our data demonstrate for the first time that EYA: 1) requires the N-terminal region of the SIX1 Six domain for its interaction, 2) increases the level of the SIX1 protein within the cell, and 3) increases the DNA binding affinity of SIX1.

| S-EPMC2742842 | biostudies-literature

A novel mutation in EYA1 in a Chinese family with Branchio-oto-renal syndrome.

Project description:BackgroundBranchio-oto-renal (BOR) syndrome is a dominant autosomal disorder characterized by phenotypes such as hearing loss, branchial fistulae, preauricular pits, and renal abnormalities. EYA1, the human homolog of the Drosophila "eye absent" gene on chromosome 8q13.3, is recognized as one of the most important genes associated with BOR syndrome.MethodsThe proposita in this study was a 5-year-old Chinese girl with hearing loss, bilateral otitis media with effusion, microtia, facial hypoplasia, palatoschisis, and bilateral branchial cleft fistulae. The girl's family members, except two who were deceased, agreed to undergo clinical examination. We collected blood samples from 10 family members, including six who were affected by the syndrome. Genomic DNA was extracted and subjected to Sanger sequencing. A minigene assay was performed to confirm whether splicing signals were altered. In addition, we performed western blotting to determine alterations in protein levels of the wild-type and mutant gene.ResultsClinical tests showed that some of the family members met the criteria for BOR syndrome. The affected members harbored a novel heterozygous nonsense variation in exon 11 of EYA1, whereas no unaffected member carried the mutation at this position. Functional experiments did not detect abnormal splicing at the RNA level; however, western blotting showed that the mutated protein was truncated.ConclusionsThis study reports a novel mutation associated with BOR syndrome in a Chinese family. We highlight the usefulness of genetic testing in the diagnosis of BOR syndrome. Thus, we believe that this report would benefit clinicians in this field.

| S-EPMC6081847 | biostudies-literature

SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.

Project description:Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.

| S-EPMC419562 | biostudies-literature

HERV-mediated genomic rearrangement of EYA1 in an individual with branchio-oto-renal syndrome.

Project description:Branchio-oto-renal syndrome is characterized by branchial defects, hearing loss, preauricular pits, and renal anomalies. Mutations in EYA1 are the most common cause of branchio-oto-renal and branchio-otic syndromes. Large chromosomal aberrations of 8q13, including complex rearrangements occur in about 20% of these individuals. However, submicroscopic deletions and the molecular characterization of genomic rearrangements involving the EYA1 gene have rarely been reported. Using the array-comparative genomic hybridization, we identified non-recurrent genomic deletions including the EYA1 gene in three patients with branchio-oto-renal syndrome, short stature, and developmental delay. One of these deletions was mediated by two human endogenous retroviral sequence blocks, analogous to the AZFa microdeletion on Yq11, responsible for male infertility. This report describes the expanded phenotype of individuals, resulting from contiguous gene deletion involving the EYA1 gene and provides a molecular description of the genomic rearrangements involving this gene in branchio-oto-renal syndrome.

| S-EPMC3605882 | biostudies-literature

A Perihilar Variant of Focal Segmental Glomerulosclerosis Due to De novo Branchio-oto-renal Syndrome.

Project description:Branchio-oto-renal syndrome is an autosomal dominant disorder characterized by branchial anomalies, hearing loss, and renal urinary tract malformations. We herein report a 32-year-old Japanese man with a right preauricular pit, bilateral mixed hearing loss, and malposition of the right kidney who presented with proteinuria. The findings of a left kidney biopsy were compatible with a perihilar variant of secondary focal segmental glomerular sclerosis. A trio exome analysis conducted among the patient and his parents failed to identify the causal gene variant, despite a sporadic pattern. His kidney function remained stable for 11 years with an angiotensin II receptor blocker.

| S-EPMC9334246 | biostudies-literature

Atypical features in two adult patients with Cockayne syndrome and analysis of genotype-phenotype correlation.

Project description: Not available

| S-EPMC10476805 | biostudies-literature

Anatomical Changes and Audiological Profile in Branchio-oto-renal Syndrome: A Literature Review.

Project description:Introduction?Branchio-oto-renal (BOR) syndrome is an autosomal-dominant genetic condition with high penetrance and variable expressivity, with an estimated prevalence of 1 in 40,000. Approximately 40% of the patients with the syndrome have mutations in the gene EYA1, located at chromosomal region 8q13.3, and 5% have mutations in the gene SIX5 in chromosome region 19q13. The phenotype of this syndrome is characterized by preauricular fistulas; structural malformations of the external, middle, and inner ears; branchial fistulas; renal disorders; cleft palate; and variable type and degree of hearing loss. Aim?Hearing loss is part of BOR syndrome phenotype. The aim of this study was to present a literature review on the anatomical aspects and audiological profile of BOR syndrome. Data Synthesis?Thirty-four studies were selected for analysis. Some aspects when specifying the phenotype of BOR syndrome are controversial, especially those issues related to the audiological profile in which there was variability on auditory standard, hearing loss progression, and type and degree of the hearing loss. Mixed loss was the most common type of hearing loss among the studies; however, there was no consensus among studies regarding the degree of the hearing loss.

| S-EPMC4296951 | biostudies-other

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

Project description:BackgroundBranchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by branchial arch anomalies, hearing loss, and kidney defects. Mutations in the human EYA1 gene have been reported associated with BOR syndrome. Here we identified that a novel variant, EYA1: NM_000503.4: c.827-1G > C (Intron 8, shear mutation) was associated with BOR in a fetus of a Chinese family.Case presentationPrenatal ultrasound examination showed that both kidneys of the fetus were small and the echo of both kidneys was enhanced. The amount of amniotic fluid was normal, and no other structural abnormalities of the fetus were found. Fetal umbilical cord blood puncture was performed. No abnormality was found in karyotyping and chromosomal microarray analysis (CMA) results. Thus, we performed a trio-based whole exome sequencing (WES), and found that the fetus carried a novel homozygous variant, EYA1: NM_000503.4: c.827-1G > C (Intron 8, shear mutation), but the parents do not have this mutation. The variation sites of fetus and parents were verified by Sanger sequencing to clarify the source of pathogenic variation.ConclusionCombined with fetal imaging examination, the novel variation of EYA1: NM_000503.4: c.827-1G > C is the cause of fetal renal dysplasia. This case report indicates that the early use of appropriate technology can clarify the etiology of fetal disease and guide prognosis consultation.

| S-EPMC9622624 | biostudies-literature

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