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Scientific Reports Jul 2023Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial...
Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype-phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five SIX1 heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with SIX1 variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with SIX1 variants, compared to 15 BOR/BO syndrome families with EYA1 variants. All SIX1 variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of SIX1 variants in South Korea, expanding the genotypic and phenotypic spectrum of SIX1 variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of SIX1 variants according to the EYA1-SIX1-DNA complex theory.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Protein Tyrosine Phosphatases; Mutation; Pedigree; Branchio-Oto-Renal Syndrome; Phenotype; Republic of Korea; Deafness; DNA; Homeodomain Proteins
PubMed: 37479820
DOI: 10.1038/s41598-023-38909-w -
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 -
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 -
Disease Models & Mechanisms Feb 2024The association between ear and kidney anomalies has long been recognized. However, little is known about the underlying mechanisms. In the last two decades, embryonic...
The association between ear and kidney anomalies has long been recognized. However, little is known about the underlying mechanisms. In the last two decades, embryonic development of the inner ear and kidney has been studied extensively. Here, we describe the developmental pathways shared between both organs with particular emphasis on the genes that regulate signalling cross talk and the specification of progenitor cells and specialised cell types. We relate this to the clinical features of oto-renal syndromes and explore links to developmental mechanisms.
Topics: Humans; Branchio-Oto-Renal Syndrome; Kidney; Kidney Diseases; Organogenesis; Embryonic Development
PubMed: 38353121
DOI: 10.1242/dmm.050447 -
Medicine Nov 2023Branchiooculofacial syndrome (BOFS) is a rare autosomal dominant disorder with a diverse clinical phenotype. To summarise the clinical characteristics and genetic... (Review)
Review
RATIONALE
Branchiooculofacial syndrome (BOFS) is a rare autosomal dominant disorder with a diverse clinical phenotype. To summarise the clinical characteristics and genetic variations of neonatal-onset BOFS through a case study and literature review.
PATIENT CONCERNS
A preterm neonate with a very low birth weight, born at a gestational age of 29+3 weeks, exhibited cosmetic abnormalities at a postmenstrual age of 34+6 weeks, including microcleft lip, high arched palate, curved upper lip, low ear position, and ocular hypertelorism. Hence, a genetic test on peripheral blood was carried out.
DIAGNOSES
The genetic testing showed a heterozygous variant of c.724G > A (p.Glu242Lys) in the exon 4 region of the TFAP2A (transcription factor AP-2-α) gene in the short arm of chromosome 6. BOFS was confirmed based on clinical appearance and the genetic result.
INTERVENTIONS
The patient underwent solely cleft lip repair at the age of 6 months with no further intervention.
OUTCOMES
The infant shows normal growth and development at 1 year of age and subsequent follow-up.
LESSONS
The characteristic facial features, branchial skin defects, and ocular anomalies are the main clinical manifestations of BOFS with neonatal onset, but the diverse clinical phenotype and variable genetic variants pose certain challenges for clinical diagnosis.
Topics: Infant; Infant, Newborn; Humans; Branchio-Oto-Renal Syndrome; Phenotype; Exons; Cleft Lip; Mutation; Transcription Factor AP-2
PubMed: 37932997
DOI: 10.1097/MD.0000000000034962 -
Journal of Molecular Neuroscience : MN Dec 2023Otofaciocervical syndrome (OTFCS) is a rare genetic disorder of both autosomal recessive and autosomal dominant patterns of inheritance. It is caused by biallelic or...
Otofaciocervical syndrome (OTFCS) is a rare genetic disorder of both autosomal recessive and autosomal dominant patterns of inheritance. It is caused by biallelic or monoallelic mutations in PAX1 or EYA1 genes, respectively. Here, we report an OTFCS2 female patient of 1st consanguineous healthy parents. She manifested facial dysmorphism, hearing loss, intellectual disability (ID), and delayed language development (DLD) as the main clinical phenotype. The novel homozygous variant c.1212dup (p.Gly405Argfs*51) in the PAX1 gene was identified by whole exome sequencing (WES), and family segregation confirmed the heterozygous status of the mutation in the parents using the Sanger sequencing. The study recorded a novel PAX1 variant representing the sixth report of OTFCS2 worldwide and the first Egyptian study expanding the geographic area where the disorder was confined.
Topics: Female; Humans; Branchio-Oto-Renal Syndrome; Exome; Genes, Recessive; Intellectual Disability; Mutation; Pedigree
PubMed: 37924468
DOI: 10.1007/s12031-023-02170-7