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BMC Nephrology Aug 2023Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop...
BACKGROUND
Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited.
CASE PRESENTATION
Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying.
CONCLUSIONS
BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.
Topics: Child, Preschool; Humans; Child; Branchio-Oto-Renal Syndrome; Renal Insufficiency; Kidney; Proteinuria; Albuminuria; Glomerulonephritis
PubMed: 37612603
DOI: 10.1186/s12882-023-03193-3 -
Neural Plasticity 2021Branchio-oto-renal spectrum disorder (BORSD) is characterized by hearing loss accompanied by ear malformations, branchial cysts, and fistulae, with (branchio-oto-renal...
Branchio-oto-renal spectrum disorder (BORSD) is characterized by hearing loss accompanied by ear malformations, branchial cysts, and fistulae, with (branchio-oto-renal syndrome (BORS)) or without renal abnormalities (BOS (branchio-otic syndrome)). As the most common causative gene for BORSD, dominant mutations in are responsible for approximately 40% of the cases. In a sporadic deaf patient diagnosed as BOS, we identified an apparent heterozygous genomic deletion spanning the first four coding exons and one 5' noncoding exon of by targeted next-generation sequencing of 406 known deafness genes. Real-time PCR at multiple regions of confirmed the existence of this genomic deletion and extended its 5' boundary beyond the 5'-UTR. Whole genome sequencing subsequently located the 5' and 3' breakpoints to 19268 bp upstream to the ATG initiation codon and 3180 bp downstream to exon 5. PCR amplification across the breakpoints in both the patient and his parents showed that the genomic alteration occurred . Sanger sequencing of this PCR product revealed that it is in fact a GRCh38/hg38:chr8:g.71318554_71374171delinsTGCC genomic deletion-insertion. Our results showed that the genomic variant is responsible for the hearing loss associated with BOS and provided an example for deciphering such cryptic genomic alterations following pipelines of comprehensive exome/genome sequencing and designed verification.
Topics: 5' Untranslated Regions; Branchio-Oto-Renal Syndrome; Child; Codon; Deafness; Exons; Gene Deletion; Hearing Loss; Hearing Loss, Sensorineural; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Intracellular Signaling Peptides and Proteins; Male; Mutagenesis, Insertional; Nuclear Proteins; Pedigree; Polymerase Chain Reaction; Protein Tyrosine Phosphatases
PubMed: 33880118
DOI: 10.1155/2021/5524381 -
Molecular Genetics & Genomic Medicine Jul 2022Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant...
BACKGROUND
Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent.
METHODS
After a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis.
RESULTS
Eight individuals from a large non-consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post-lingual and mixed type of HI, one individual had conductive HI while three had normal hearing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A > G; p.Asp429Gly) segregating with BO syndrome in the family.
CONCLUSION
This is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub-Saharan African population, expanding the genetic spectrum of the condition.
Topics: Adolescent; Adult; Branchio-Oto-Renal Syndrome; Child; Hearing Loss; Humans; Intracellular Signaling Peptides and Proteins; Middle Aged; Nuclear Proteins; Pedigree; Protein Tyrosine Phosphatases; Young Adult
PubMed: 35698919
DOI: 10.1002/mgg3.1995 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2022Microtia is the second most common maxillofacial birth defect in neonates and has an prevalence rate of 3.06/10 000 in China, and 20%-60% of microtia cases is associated...
Microtia is the second most common maxillofacial birth defect in neonates and has an prevalence rate of 3.06/10 000 in China, and 20%-60% of microtia cases is associated with a certain type of syndrome. This article elaborates on the clinical phenotypes and genetic characteristics of three microtia-associated syndromes (MASs) with high prevalence, high incidence rate of ear deformity, and definite genetic etiology, i.e., oculo-auriculo-vertebral spectrum, branchio-oto-renal spectrum disorder, and Treacher-Collins syndrome, and summarizes another three common MASs, so as to provide a reference for the genetic diagnosis of neonatal MAS.
Topics: China; Congenital Microtia; Humans; Infant, Newborn; Phenotype; Prevalence; Syndrome
PubMed: 35762425
DOI: 10.7499/j.issn.1008-8830.2203008 -
Development (Cambridge, England) Sep 2021Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its...
Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its co-factor Eya1, both of which are required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 co-factor, and SOBP variants in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-immunoprecipitation and immunofluorescence experiments demonstrate that Sobp binds to and colocalizes with Six1 in the cell nucleus. Luciferase assays show that Sobp interferes with the transcriptional activation of Six1+Eya1 target genes. Experiments in Xenopus embryos that either knock down or increase expression of Sobp show that it is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human variant disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function and is required for vertebrate craniofacial development, and identify Sobp as a potential candidate gene for BOR.
Topics: Animals; Bone Development; Branchio-Oto-Renal Syndrome; Cell Nucleus; Ear, Inner; Ectoderm; Gene Expression; Homeodomain Proteins; Larva; Metalloproteins; Neural Crest; Nuclear Proteins; Protein Binding; Protein Tyrosine Phosphatases; Transcriptional Activation; Xenopus Proteins; Xenopus laevis
PubMed: 34414417
DOI: 10.1242/dev.199684 -
BMC Pediatrics Nov 2022Branchio-Oto-Renal (BOR) Syndrome is a rare autosomal disorder with a wide variety of clinical manifestations and a high degree of heterogeneity. Typical clinical...
BACKGROUND
Branchio-Oto-Renal (BOR) Syndrome is a rare autosomal disorder with a wide variety of clinical manifestations and a high degree of heterogeneity. Typical clinical manifestations of BOR syndrome include deafness, preauricular fistula, abnormal gill slits, and renal malformations. However, atypical phenotypes such as congenital hip dysplasia, congenital heart anomaly or facial nerve paresis are rare in BOR syndrome, and this might be easily misdiagnosed with other congenital disorders.
CASE PRESENTATION
We report a 5-month-old boy of BOR syndrome with "congenital heart defects and proteinuria" as clinical features. Initially, as this case mainly presented with symptoms of recurrent respiratory infections and was found to be with congenital heart disease and proteinuria at the local hospital, but he only was diagnosed with congenital heart disease combined with pulmonary infection and anti-infective and supportive treatment was given. Subsequently, during the physical examination at our hospital, left side preauricular pit and branchial fistulae on the right neck were found. Subsequent evaluation of auditory brainstem response and distortion product otoacoustic emission were revealed sensorineural hearing impairment. Results of renal ultrasonography showed small kidneys. Genetic analysis revealed a microdeletion at chromosome 8q13.2-q13.3 encompassing EYA1 gene, this patient was finally diagnosed with BOR syndrome. Then, this patient received transcatheter patent ductus arteriosus closure and hearing aid treatment. Proteinuria, renal function and hearing ability are monitoring by nephrologist and otologist. The patient is currently being followed up until 3 months after discharge and his condition is stable.
CONCLUSION
Careful physical examination, detailed history and the implementation of diagnostic laboratory tests can reduce the incidence of misdiagnosis. Genetic sequencing analysis of patients is a key guide to the differential diagnosis of BOR syndrome.
Topics: Male; Humans; Branchio-Oto-Renal Syndrome; Pedigree; Phenotype; Proteinuria; Heart Defects, Congenital
PubMed: 36333735
DOI: 10.1186/s12887-022-03705-4 -
BMC Medical Genomics Apr 2024Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural,...
OBJECTIVE
Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms.
METHODS
The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments.
RESULTS
Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic.
CONCLUSION
This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.
Topics: Humans; Pregnancy; Female; Branchio-Oto-Renal Syndrome; Intracellular Signaling Peptides and Proteins; Protein Tyrosine Phosphatases; Hearing Loss; Deafness; Hearing Loss, Sensorineural; Renal Insufficiency; Pedigree; Nuclear Proteins
PubMed: 38627775
DOI: 10.1186/s12920-024-01858-y -
Italian Journal of Pediatrics Oct 2022Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by deafness, branchiogenic malformations and renal abnormalities. Pathogenic variants...
BACKGROUND
Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by deafness, branchiogenic malformations and renal abnormalities. Pathogenic variants in EYA1, SIX1 and SIX5 genes cause almost half of cases; copy number variants (CNV) and complex genomic rearrangements have been revealed in about 20% of patients, but they are not routinely and commonly included in the diagnostic work-up.
CASE PRESENTATION
We report two unrelated patients with BOR syndrome clinical features, negative sequencing for BOR genes and the identification of a 2.65 Mb 8q13.2-13.3 microdeletion.
CONCLUSIONS
We highlight the value of CNV analyses in high level of suspicion for BOR syndrome but negative sequencing for BOR genes and we propose an innovative diagnostic flow-chart to increase current detection rate. Our report confirms a mechanism of non-allelic homologous recombination as causing this recurrent 8q13.2-13.3 microdeletion. Moreover, considering the role of PRDM14 and NCOA2 genes, both involved in regulation of fertility and deleted in our patients, we suggest the necessity of a longer follow-up to monitor fertility issues or additional clinical findings.
Topics: Branchio-Oto-Renal Syndrome; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Pedigree; Protein Tyrosine Phosphatases
PubMed: 36183088
DOI: 10.1186/s13052-022-01369-5 -
Internal Medicine (Tokyo, Japan) Jul 2022Branchio-oto-renal syndrome is an autosomal dominant disorder characterized by branchial anomalies, hearing loss, and renal urinary tract malformations. We herein report...
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.
Topics: Adult; Branchio-Oto-Renal Syndrome; Deafness; Glomerulosclerosis, Focal Segmental; Hearing Loss; Humans; Kidney; Male
PubMed: 34866102
DOI: 10.2169/internalmedicine.8508-21 -
Pediatric Nephrology (Berlin, Germany) Jun 2020The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our... (Review)
Review
The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.
Topics: Adolescent; Age Factors; Branchio-Oto-Renal Syndrome; Child; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Kidney Failure, Chronic; Male; Middle Aged; Mutation; Pedigree; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Exome Sequencing
PubMed: 31049720
DOI: 10.1007/s00467-019-04266-y