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Branchiootorenal Spectrum Disorders

, MD
Director, Molecular Otolaryngology Research Laboratories
Sterba Hearing Research Professor of Otolaryngology
Professor of Otolaryngology, Pediatrics, and Internal Medicine, Division of Nephrology
Carver College of Medicine
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: October 22, 2015.

Summary

Clinical characteristics.

Branchiootorenal spectrum disorders comprise branchiootorenal (BOR) syndrome and branchiootic syndrome (BOS).

  • BOR is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease (ESRD) later in life.
  • BOS has the same features as BOR syndrome but without renal involvement.

Extreme variability can be observed in the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality from right side to left side in an affected individual and also among individuals in the same family. BOR syndrome and BOS can be seen in the same family.

Diagnosis/testing.

The diagnosis of branchiootorenal spectrum disorders is based on clinical criteria. Molecular genetic testing of EYA1 (BOR1, BOS1) detects pathogenic variants in approximately 40% of individuals with the clinical diagnosis of BOR/BOS. Pathogenic variants can be detected in an additional 5% and 4% of individuals with the clinical diagnosis of BOR/BOS by molecular genetic testing of SIX5 (BOR2) and SIX1 (BOR3, BOS3), respectively.

Management.

Treatment of manifestations: Excision of branchial cleft cysts/fistulae, fitting with appropriate aural habilitation, and enrollment in appropriate educational programs for the hearing impaired are appropriate. A canaloplasty should be considered to correct an atretic external auditory canal. Medical and surgical treatment for vesicoureteral reflux may be necessary. End-stage renal disease (ESRD) may require dialysis or renal transplantation.

Surveillance: Semiannual examination for hearing impairment and annual audiometry to assess stability of hearing loss; monitoring of renal function to prevent progression to ESRD; semiannual/annual examination by a nephrologist and/or urologist, as indicated.

Agents/circumstances to avoid: Nephrotoxic medications.

Evaluation of relatives at risk: At-risk relatives should be screened for hearing loss and renal involvement to allow for early diagnosis and treatment.

Genetic counseling.

BOR syndrome and BOS are inherited in an autosomal dominant manner. The offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant. Prenatal testing for pregnancies at risk is possible if the pathogenic variant has been identified in a family member.

GeneReview Scope

Branchiootorenal Spectrum Disorders: Included Phenotypes
  • Branchiootorenal (BOR) syndrome
  • Branchiootic syndrome (BOS)

For synonyms and outdated names see Nomenclature.

Diagnosis

Branchiootorenal spectrum disorders (BOR/BOS) comprise branchiootorenal (BOR) syndrome and branchiootic syndrome (BOS).

Suggestive Findings

Branchiootorenal spectrum disorders (BOR/BOS) should be suspected in individuals with the following characteristics:

Branchiootorenal (BOR) Syndrome

In the absence of a family history, three or more of the following major criteria OR two major and two minor criteria (see Table 1) must be present to make the clinical diagnosis of BOR syndrome [Chang et al 2004]:

Table 1.

Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome

Major CriteriaMinor Criteria
Second branchial arch anomalies
Deafness
Preauricular pits
Auricular malformation
Renal anomalies
External auditory canal anomalies
Middle ear anomalies
Inner ear anomalies
Preauricular tags
Other: facial asymmetry, palate abnormalities

Second branchial arch anomalies

  • Branchial cleft sinus tract appearing as a pin-point opening anterior to the sternocleidomastoid muscle, usually in the lower third of the neck
  • Branchial cleft cyst appearing as a palpable mass under the sternocleidomastoid muscle, usually above the level of the hyoid bone

Otologic findings

  • Deafness: mild to profound in degree; conductive, sensorineural, or mixed in type (see Deafness and Hereditary Hearing Loss Overview)
  • Preauricular pits
  • Auricular malformation (lop ear, cupped ear)
  • Preauricular tags
  • Abnormalities of the external auditory canal: atresia or stenosis
  • Middle ear abnormalities: malformation, malposition, dislocation, or fixation of the ossicles; reduction in size or malformation of the middle ear space
  • Inner ear abnormalities: cochlear hypoplasia; enlargement of the cochlear and vestibular aqueducts; hypoplasia of the lateral semicircular canal [Ceruti et al 2002, Kemperman et al 2002]

Renal anomalies

  • Renal agenesis, hypoplasia, dysplasia
  • Uretero-pelvic junction (UPJ) obstruction
  • Calyceal cyst/diverticulum
  • Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux

Note: Individuals with an affected family member need only one major criterion to make the diagnosis of BOR syndrome [Chang et al 2004].

Branchiootic Syndrome (BOS)

In the absence of structural renal anomalies, the clinical diagnosis of BOS should be considered. BOS is characterized by the presence of hearing loss, cupped ear malformation, preauricular pits, and branchial fistulae and the absence of renal anomalies.

Establishing the Diagnosis

The diagnosis of a branchiootorenal spectrum disorder is established in a proband with the clinical features listed above and/or identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and genomic testing.

  • Serial single-gene testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the disease or (2) clinical findings, laboratory findings, ancestry, and related factors indicate that mutation of a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes EYA1, SIX5, SIX1, and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of BOR/BOS. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    For issues to consider in interpretation of genomic test results, click here.

Clinical testing

Table 2.

Summary of Molecular Genetic Testing Used in Branchiootorenal Spectrum Disorders (BOR/BOS)

Gene 1Proportion of BOR/BOS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
EYA140% 580%20%
SIX52.5% 6100%None reported
SIX12% 7100%None reported
Unknown 8NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

Heterozygous pathogenic variants were identified in 5/95 (5.2%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX1 pathogenic variant was not identified [Hoskins et al 2007]; these data imply a SIX5 mutation rate of fewer than 2.5% of persons with BOR syndrome.

7.

Heterozygous pathogenic variants were identified in 10/247 (4.0%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX5 pathogenic variant was not identified [Kochhar et al 2008]. This prevalence implies that SIX1 pathogenic variants account for approximately 2% of cases of BOR syndrome.

8.

Clinical Characteristics

Clinical Description

Branchiootorenal spectrum disorders include branchiootorenal (BOR) syndrome and branchiootic syndrome (BOS).

BOR Syndrome

The presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality in BOR syndrome may differ from right side to left side in an affected individual and among individuals in the same family.

Second branchial arch anomalies include branchial cleft cyst or sinus tract (cervical fistulae) (50%). Cysts can become infected and sinus tracts can drain.

Otologic findings, found in more than 90% of individuals with BOR syndrome [Chang et al 2004], include:

  • Hearing loss (>90%) [Stinckens et al 2001]
    • Type: mixed (52%), conductive (33%), sensorineural (29%)
    • Severity: mild (27%), moderate (22%), severe (33%), profound (16%)
    • Non-progressive (~70%), progressive (~30%, correlates with presence of a dilated vestibular aqueduct on computed tomography) [Kemperman et al 2004]
  • Abnormalities of the pinnae
    • Preauricular pits (82%)
    • Lop ear malformation (36%)
    • Preauricular tags (13%)
  • Abnormalities of the external auditory canal. Atresia or stenosis (29%)
  • Middle ear abnormalities. Malformation, malposition, dislocation, or fixation of the ossicles; reduction in size or malformation of the middle ear space
  • Inner ear abnormalities. Variably present:

Renal anomalies. Renal malformations can be unilateral or bilateral and can occur in any combination. The most severe malformations result in pregnancy loss (since bilateral renal agenesis can end in miscarriage) or neonatal death; ESRD later in life may necessitate dialysis or transplantation.

Although renal anomalies are common, the true prevalence is difficult to establish because not all affected individuals undergo intravenous pyelography or renal ultrasonography. In a study in which 21 affected individuals had one of these two tests, renal anomalies were noted in 67% [Chang et al 2004] and included the following:

  • Renal agenesis (29%), hypoplasia (19%), dysplasia (14%)
  • Uretero-pelvic junction (UPJ) obstruction (10%)
  • Calyceal cyst/diverticulum (10%)
  • Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux (5% each)

Other findings [Chang et al 2004]

  • Lacrimal duct aplasia
  • Short or cleft palate
  • Retrognathia
  • Euthyroid goiter
  • Facial nerve paralysis
  • Gustatory lacrimation

Branchiootic Syndrome (BOS)

BOS can be caused by allelic variants of EYA1, and is characterized by deafness, cupped ear malformation, preauricular pits, and branchial fistulae, in the absence of renal anomalies. In two families with BOS and pathogenic variants in EYA1, affected individuals had sensorineural (25%), mixed (66%), or conductive (9%) hearing loss; branchial fistulae (100%); preauricular pits (80%); and cupped ear malformation (60%) [Chang et al 2004].

Genotype-Phenotype Correlations

A genotype-phenotype correlation has not been defined for BOR/BOS. To compare phenotype with genotype, Zhang et al [2004] grouped EYA1 pathogenic variants as inactivating (i.e., splice site variants, insertions, nonsense variants, and duplications and deletions of >3 bp) or non-inactivating (i.e., pathogenic missense variants and 3-bp deletions). Using this criterion, they showed that EYA1 inactivating variants are not associated with a more severe phenotype (p=0.799).

Mice with a targeted deletion of the ortholog Six1 display a wide range of phenotypes. When the mutant Six1 protein is not expressed, the presence of a phenotype depends on the genetic background [Xu et al 2003]. For example, murine deletions in Six1 modify the severity of the phenotype caused by deletions in the ortholog Eya1 [Li et al 2003, Xu et al 2003, Zheng et al 2003]. This type of double heterozygosity has not been described in persons with a BOR/BOS phenotype. However, of families reported with SIX1 pathogenic variants, only two have renal abnormalities, suggesting that genetic background significantly affects the severity of renal defects in BOR syndrome.

Other explanations for the range of phenotypes include haploinsufficiency and dominant-negative or gain-of-function effects. Of these possibilities, when considering SIX1 and SIX5 pathogenic variants, complex dominant-negative and/or gain-of-function mechanisms are appealing, as no inactivating variants (i.e., splice site variants, insertions, nonsense variants, and duplications and deletions of >3 bp) have been reported in families with branchiootorenal spectrum disorders and pathogenic variants in SIX1 or SIX5 [Hoskins et al 2007, Kochhar et al 2008].

A parent-of-origin effect does not appear to be present: renal defects have been reported in six live-born offspring of affected fathers and four live-born offspring of affected mothers.

Penetrance

Based on careful clinical studies of large pedigrees, branchiootorenal spectrum disorders appear to have 100% penetrance, although expressivity is highly variable [Chang et al 2004].

Nomenclature

BOR syndrome is known eponymously as Melnick-Fraser syndrome. While phenotypic descriptions are applied to BOR, BOS, and even branchiootoureteral (BOU) syndrome, these clinical distinctions must be considered in light of the associated molecular genetics. Many affected persons in families segregating EYA1 pathogenic variants have clinical findings consistent with the diagnosis of BOR; however, some affected persons in these same families have clinical findings consistent with BOS or BOU [Orten et al 2008]. For this reason, these syndromes are best considered as branchiootorenal spectrum disorders.

Prevalence

The prevalence of branchiootorenal spectrum disorders is not known. In 1976, GR Fraser surveyed 3,640 children with profound hearing impairment and found only five (0.15%) with a family history of branchial fistulae and preauricular pits (1:700,000) [Fraser 1976]. Four years later, in a study by FC Fraser of 421 children in the Montreal School for the Deaf, 2% of the profoundly deaf students had BOR syndrome [Fraser et al 1980]. Using these data, Fraser et al [1980] estimated the prevalence of BOR syndrome at 1:40,000. The true prevalence is probably somewhere between these extremes.

Differential Diagnosis

More than 400 genetic syndromes that include hearing loss have been described [Toriello et al 2004]. Although the branchiootorenal spectrum disorders have a distinctive phenotype that is readily appreciated when segregating in large families, the diagnosis can be more difficult to establish in small families. See Deafness and Hereditary Hearing Loss Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a branchiootorenal spectrum disorder (BOR/BOS), the following evaluations are recommended:

  • Second branchial arch anomalies. Cervical examination for fistulae; computed tomography of the neck if a mass is palpable under the sternocleidomastoid muscle above the level of the hyoid bone
  • Otologic findings
    • A complete assessment of auditory acuity using ABR, emission testing, and pure tone audiometry (see Deafness and Hereditary Hearing Loss Overview)
    • Computed tomography of the temporal bones, especially if the hearing impairment fluctuates or is progressive
  • Renal anomalies. Renal ultrasound examination and/or excretory urography (intravenous pyelography); tests of renal function: BUN and creatinine; urinanalysis
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Recommended treatment:

  • Second branchial arch anomalies. Excise branchial cleft cysts/fistulae.
  • Otologic anomalies
    • Fit with appropriate aural habilitation as indicated.
    • Enroll in an appropriate educational program for the hearing impaired.
    • Consider canaloplasty to correct an atretic canal; however, in individuals with BOR/BOS, associated middle ear anomalies (e.g., a facial nerve overriding the oval window) can preclude a successful result. Evaluate the status of the middle ear preoperatively by obtaining thin-cut CT images of the temporal bones in both the axial and coronal planes.
  • Renal anomalies
    • Treat urologic and renal abnormalities in the standard manner.
    • If renal anomalies (e.g., vesicoureteral reflux) are present, medical and surgical treatment may prevent progression to end-stage renal disease (ESRD).
    • If ESRD develops, consider renal transplantation.

Prevention of Primary Manifestations

Otologic manifestations of disease can often be surgically corrected with correction of the cupped-ear malformation and occasionally improvement in the conductive component of the hearing loss.

Branchial arch anomalies can be surgically corrected.

Prevention of Secondary Complications

Renal anomalies such as vesicoureteral reflux can lead to progressive renal failure, a secondary complication that can be avoided by surgical correction of retrograde flow of urine from the bladder into the ureter.

Surveillance

Surveillance for otologic and renal anomalies should be offered as described below.

Otologic anomalies. Serial audiometry to survey for progression of hearing loss:

  • Annual examination by a physician who is familiar with hereditary hearing impairment
  • Semiannual examination for hearing impairment and annual audiometry to assess stability of hearing loss (more frequent if fluctuation or progression is described by the affected individual)

Renal anomalies

  • Regular assessment of renal function to prevent progression to ESRD
  • Semiannual/annual examination by a nephrologist and/or urologist if indicated, based on level of renal function and type of renal and/or collecting system malformation

Agents/Circumstances to Avoid

Individuals with renal abnormalities should use appropriate caution when taking medications (i.e., antibiotics and analgesics) that can impair renal function or require normal renal physiology for clearance.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic relatives at risk for BOR/BOS to determine if a treatable and/or possibly progressive otologic and/or renal abnormality is present.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • Comprehensive physical examination (to include hearing evaluation and renal imaging and function studies) if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The branchiootorenal spectrum disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 90% of individuals diagnosed with a branchiootorenal spectrum disorder have an affected parent.
  • A proband with a branchiootorenal spectrum disorder may have the disorder as the result of a de novo EYA1, SIX5, or SIX1 pathogenic variant. Approximately 10% of cases are caused by de novo pathogenic variants.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing for the pathogenic variant identified in the proband and examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and renal anomalies. An apparently negative family history cannot be confirmed until appropriate evaluation of the parents has been performed.

Note: Although most individuals diagnosed with a branchiootorenal spectrum disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parents.
  • If a parent is diagnosed with a branchiootorenal spectrum disorder, the risk to each sib is 50%.
  • Disease severity cannot be accurately predicted and is extremely variable even within the same family.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the EYA1, SIX5, or SIX1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with a branchiootorenal spectrum disorder has a 50% chance of inheriting the EYA1, SIX5, or SIX1 pathogenic variant.
  • Disease severity cannot be accurately predicted and is extremely variable even within the same family.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the EYA1, SIX5, or SIX1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene of interest or custom prenatal testing.

Fetal ultrasound examination. For fetuses at increased risk for BOR syndrome, prenatal ultrasound examination at 16-17 weeks' gestation should be considered for evaluation of significant renal malformations and/or oligohydramnios.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

While requests for prenatal testing for significant medical conditions such as bilateral renal agenesis are generally accepted, requests for prenatal testing for conditions such as BOR syndrome may be more problematic. Variable expressivity makes it impossible to accurately predict which manifestations of BOR syndrome may occur and how mild or severe they will be. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the EYA1, SIX5, or SIX1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Kidney Foundation of Canada
    310-5160 Decarie Blvd.
    Montreal Ontario H3X 2H9
    Canada
    Phone: 800-361-7494 (toll-free); 514-369-4806
    Fax: 514-369-2472
    Email: info@kidney.ca
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Email: info@kidney.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Branchiootorenal Spectrum Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Branchiootorenal Spectrum Disorders (View All in OMIM)

113650BRANCHIOOTORENAL SYNDROME 1; BOR1
600963SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 5; SIX5
601205SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 1; SIX1
601653EYES ABSENT 1; EYA1
602588BRANCHIOOTIC SYNDROME 1; BOS1
608389BRANCHIOOTIC SYNDROME 3; BOS3
610896BRANCHIOOTORENAL SYNDROME 2; BOR2

Molecular Genetic Pathogenesis

The vertebrate Eya gene family comprises four transcriptional activators that interact with other proteins in a conserved regulatory hierarchy to ensure normal embryologic development. The structure of these proteins includes a highly conserved 271-amino acid carboxy terminus called the eya-homologous region (eyaHR) and a more divergent proline-serine-threonine (PST)-rich (34%-41%) transactivation domain at the amino terminus (eya variable region, eyaVR) [Zhang et al 2004].

Studies in Drosophila indicate that the eyaHR mediates interactions with the gene products of so (sine oculis) and dac (dachshund), and that expression of both eya and so is initiated by ey (eyeless). The vertebrate orthologs of so are members of the Six gene family and similarly bind with Eya proteins, inducing nuclear translocation of the resultant protein complex. Amino terminal transcriptional activation has been demonstrated for the Drosophila eya and murine Eya1, Eya2, Eya3 gene products, an additional indication that Eya interactions and pathways are conserved across species.

Expression of Eya genes is present in a wide variety of tissues early in embryogenesis, and although each gene has a unique expression pattern, extensive overlap exists. For example, murine studies have shown that Eya1, Eya2, and Eya4 are all expressed in the presomitic mesoderm and head mesenchyme, but only Eya1 and Eya4 are expressed in the otic vesicle [Wayne et al 2001]. Eya3 expression is restricted to craniofacial and branchial arch mesenchyme in regions underlying or surrounding the cranial placodes expressing the gene product of Eya1, Eya2, or Eya4.

Six1 functions as both a transactivator and a transcriptional repressor, depending on its cofactors [Silver et al 2003, Bricaud & Collazo 2006].

EYA1

Gene structure. EYA1 consists of 16 coding exons that extend over 156 kb. It has at least four alternatively spliced transcripts. For a detailed summary of gene and protein information, see Table A, Gene.

The 5' exons (exon -1 and the 3' end of exon 1) produce an open reading frame (ORF) that could add more than 156 amino acids to the amino terminal of EYA1; however, it is not known whether this sequence is translated. The seventeen introns of EYA1 vary in size from 0.1 to 27.5 kb [Orten et al 2008].

Benign allelic variants. Numerous sequence variants of EYA1 have been reported. When allelic variants are discovered, it is not always clear whether they are disease causing. Since pathogenic variants in EYA1 are not found in 60% of people with BOR/BOS, caution must be used when interpreting the effect of pathogenic missense variants in a single family, especially if rigorous population-based studies have not been performed.

Pathogenic allelic variants. More than 80 different disease-causing allelic variants of EYA1 that result in BOR/BOS have been identified [Kumar et al 1998]. These include nonsense [Kumar et al 1998], missense, frameshift [Kumar et al 1998], and splice site variants and gross deletions and insertions. A gross deletion of ~2.7 Mbp appears to be a relatively common cause of BOR/BOS in affected persons who are negative for EYA1 coding region and splice-site pathogenic variants. The breakpoints of this deletion reside in long terminal repeat elements of the ERV1 retrovirus family [Sanchez-Valle et al 2010, Brophy et al 2013].

All of these pathogenic variants affect at least two EYA1 isoforms. In addition, the presence of pathogenic variants in exon 12 (which is skipped in the shortest transcript EYA1D, NM_172059.3) indicates that the longer isoforms are necessary for EYA1 function [Orten et al 2008]. A list of BOR-/BOS-causing variants is maintained at www.healthcare.uiowa.edu.

Normal gene product. The proteins encoded by the transcript variants EYA1A (NP_742057.1; 559 amino acids) and EYA1B (NP_742055.1; 592 amino acids) differ only in their N-terminal region. EYA1C (NM_000503.5) has two overlapping open reading frames (ORFs). One of the predicted ORFs is identical to that of EYA1B; however, for this ORF, the first stop codon is an additional 369 nucleotides upstream. The full extent of the second ORF has not been completely determined; EYA1C could give rise to two distinct proteins or alternatively the two ORFs could be translated into a single protein by ribosomal frame shifting.

The 5' UTR variations and alternate splicing are consistent with multifaceted control of EYA1 gene expression, which is particularly relevant because the protein encodes products important for inner-ear, kidney, and branchial-arch development.

Eya proteins have intrinsic phosphatase activity, enabling it to serve as a promoter-specific transcriptional co-activator. It is part of the Six-Eya-Dach regulatory network that defines a molecular mechanism by which a recruited co-activator with phosphatase function (Eya) derepresses target genes. Six1 acts as a repressor or as an activator of gene transcription based, at least in part, on the recruitment of opposing cofactors. The recruitment of Dach is associated with co-repressor activity, while the recruitment of Eya is associated with co-activator activity. The co-activator activity of Eya is based on its phosphatase activity, which reverses the co-repressor activity of Dach and permits the recruitment of other co-activators, including CREB-binding protein (CBP) [Li et al 2003].

Abnormal gene product. Some pathogenic allelic variants in EYA1 generate mutant proteins that are rapidly degraded, implying that haploinsufficiency can cause BOR/BOS [Zhang et al 2004]. These data are also consistent with the presence of large deletions of one allele of EYA1 in some families with BOR/BOS. Based on data derived from in vivo studies of the Drosophila developmental system, other pathogenic missense variants affect either phosphatase or transcription function [Mutsuddi et al 2005]. These different types of mutational effects are predicted to lead to differences in phenotype.

SIX1

Gene structure. SIX1 has a transcript of 1376 bp and two exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Eight SIX1 pathogenic variants have been reported [Ruf et al 2004, Ito et al 2006, Kochhar et al 2008]. One of these, c.328C>T, was detected in six unrelated families from multiple ethnic groups [Kochhar et al 2008].

Table 3.

SIX1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.50T>Ap.Val17GluNM_005982​.3
NP_005973​.1
c.317T>Gp.Val106Gly
c.328C>Tp.Arg110Trp
c.334C>Tp.Arg112Cys
c.386A>Gp.Tyr129Cys
c.397_399delGAGp.Glu133del

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SIX1 is one of six members of the SIX gene family (SIX1-SIX6) in humans. Like each of the transcribed proteins in this family, homeobox protein SIX1 has both a conserved SIX domain and homeodomain, which are required for DNA binding. Expression of SIX1 is necessary for normal development of the inner ear, nose, thymus, kidney, and skeletal muscle. Mice with a targeted deletion of the ortholog Six1 have been shown to have abnormalities of these organs [Ando et al 2005].

Abnormal gene product. Functional characterization of several SIX1 pathogenic variants has shown that they appear to have one of two consequences [Ohto et al 1999, Ruf et al 2004, Patrick et al 2009]:

  • Abolish SIX1-EYA1 complex formation, thus preventing nuclear localization (i.e., p.Val17Glu);
    OR
  • Abrogate DNA binding of the SIX1-EYA1 complex (i.e., p.Val106Gly, p.Arg110Trp, p.Arg112Cys, p.Tyr129Cys, p.Glu133del).

The fact that no inactivating variants have been discovered suggests that the BOR/BOS phenotype is not the result of haploinsufficiency [Ruf et al 2004].

SIX5

Gene structure. SIX5 has a transcript of 3145 bp and three exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Based on the identification of pathogenic variants in SIX5 in five of 95 unrelated individuals with BOR/BOS syndrome, at least four pathogenic variants are known [Hoskins et al 2007] (see Table 4).

Table 4.

SIX5 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.472G>Ap.Ala158ThrNM_175875​.3
NP_787071​.2
c.886G>Ap.Ala296Thr
c.1093G>Ap.Gly365Arg
c.1655C>Tp.Thr552Met

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The homeobox protein SIX5 has 739 amino acid residues and a high degree of homology to SIX1, and is known to interact directly with EYA1. However, unlike SIX1, SIX5 has an additional activation domain (AD) at the C-terminus [Hoskins et al 2007].

Abnormal gene product. In vitro data suggest that both p.Ala158Thr and p.Thr552Met residues of SIX5 may be required for efficient binding with EYA1 [Hoskins et al 2007]. Yeast two-hybrid liquid β-galactosidase assays using GAL4 BD-SIX5 and GAL4 AD-Eya1D constructs cause strong lacZ expression as a result of interaction between the two fusion proteins. The p.Ala296Thr and p.Gly365Arg pathogenic variants result in a slight reduction in lacZ expression, while both p.Ala158Thr and p.Thr552Met show more than a twofold reduction in lacZ expression.

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available online. 2002. Accessed 10-14-15.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 10-14-15.

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Chapter Notes

Author Notes

Web: Pendred/BOR Home Page

Acknowledgments

The original preparation of this manuscript was supported in part by grants 1RO1DC02842 and 1RO1DC03544. (RJHS)

Author History

Glenn E Green, MD; Arizona Health Sciences Center (1999-2001)
Sai D Prasad; University of Iowa (1999-2001)
Richard JH Smith, MD (1999-present)

Revision History

  • 22 October 2015 (me) Comprehensive update posted live
  • 20 June 2013 (me) Comprehensive update posted live
  • 27 August 2009 (me) Comprehensive update posted live
  • 27 March 2008 (cd) Revision: sequence analysis for BOR2-related SIX5 available clinically
  • 24 March 2006 (cd) Revision: prenatal testing for EYA1 mutations available
  • 24 January 2006 (me) Comprehensive update posted to live Web site
  • 30 October 2003 (me) Comprehensive update posted to live Web site
  • 28 November 2001 (me) Comprehensive update posted to live Web site
  • 19 March 1999 (pb) Review posted to live Web site
  • 6 January 1999 (rjhs) Original submission
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