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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: June 20, 2013.

Summary

Disease 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 mutations in approximately 40% of individuals with the clinical diagnosis of BOR/BOS. Mutations 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 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 end-stage renal disease (ESRD); semiannual/annual examination by a nephrologist and/or urologist, as indicated.

Agents/circumstances to avoid: Nephrotoxic mediations.

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

Genetic counseling. BOR and BOS are inherited in an autosomal dominant manner. Affected individuals have a 50% chance of transmitting the disorder to each child. Prenatal testing for fetuses at risk for BOR/BOS is possible for families in which the disease-causing mutation has been identified.

Diagnosis

Clinical Diagnosis

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

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 deformity
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 deformity (lop-ear deformity)
  • 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 deafness, cup-ear deformity, preauricular pits, and branchial fistulae and the absence of renal anomalies.

Molecular Genetic Testing

Genes. EYA1, SIX5, and SIX1 are the three genes in which mutations are known to cause branchiootorenal spectrum disorders:

  • EYA1
    • BOR1. Approximately 40% of individuals with BOR syndrome have mutations in EYA1 [Chang et al 2004].
    • BOS1. Although persons in many families segregating EYA1 mutations have renal abnormalities consistent with the clinical diagnosis of BOR, some affected persons in these families can have normal kidneys. In many individuals, the kidneys may not be evaluated, and when evaluated, although kidney malformations may be detected by urography, renal function is often normal [Orten et al 2008].
  • SIX5
    • BOR2. Approximately 5% of individuals with BOR syndrome have mutations in SIX5 [Hoskins et al 2007].
  • SIX1

Evidence for locus heterogeneity

  • BOR. It is likely that mutations in additional genes are causally related to the BOR syndrome phenotype.
  • BOS. The BOS2 locus has been withdrawn. BOS2 was originally assigned to chromosome 1q31 based on linkage data on a large extended family in which affected individuals have branchial anomalies and hearing loss associated with commissural lip pits [Kumar et al 2000]. Subsequent studies have not confirmed this localization and reexamination of affected individuals has identified some persons with renal abnormalities [Kimberling, personal communication].

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Branchiootorenal Spectrum Disorders (BOR/BOS)

Gene 1% of All BOR/BOSTest MethodMutations Detected 2
EYA140%Mutation scanningSmall insertions, small deletions, missense and nonsense mutations
Duplication/deletion analysis 3Partial- or whole-gene rearrangements 4
SIX52.5%Sequence analysis 5Sequence variants 6
SIX12%Sequence analysis 5Sequence variants 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4. In approximately 10% of individuals with BOR/BOS, a chromosomal rearrangement of the EYA1 region will be present [Chang et al 2004]. See Molecular Genetics.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Heterozygous mutations were identified in 5/95 (5.2%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX1 mutation 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 mutations were identified in 10/247 (4.0%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX5 mutation was not identified [Kochhar et al 2008]. This prevalence implies that SIX1 mutations account for approximately 2% of cases of BOR syndrome.

Testing Strategy

Confirming/establishing the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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%)
    • 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) [Stinckens et al 2001, Kemperman et al 2004]
  • Abnormalities of the pinnae
    • Preauricular pits (82%)
    • Lop-ear deformity (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, cup-ear deformity, preauricular pits, and branchial fistulae, in the absence of renal anomalies. In two families with BOS and mutations in EYA1, affected individuals had sensorineural (25%), mixed (66%), or conductive (9%) hearing loss; branchial fistulae (100%); preauricular pits (80%); and cup-ear deformity (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 mutations as inactivating (i.e., splice site mutations, insertions, nonsense mutations, and duplications and deletions of >3 bp) or non-inactivating (i.e., missense mutations and 3-bp deletions). Using this criterion, they showed that EYA1 inactivating mutations are not associated with a more severe phenotype (p=0.799).

Mouse mutants with a targeted deletion of 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, deletions in Six1 in mice modify the severity of the phenotype caused by deletions in 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 mutations, only two have renal abnormalities, a finding that suggest 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 disease-causing mutations, complex dominant-negative and/or gain-of-function mechanisms are appealing, as no inactivating mutations (i.e., splice site mutations, insertions, nonsense mutations, and duplications and deletions of >3 bp) have been reported in SIX1 or SIX5 families with branchiootorenal spectrum disorders [Hoskins et al 2007, Kochhar et al 2008].

A parent-of-origin effect does not appear to be present, as 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].

Anticipation

Although anticipation (the tendency of some dominant conditions to become more severe in successive generations) has been considered by several investigators, family studies suggest that it does not occur. For example, in seven three-generation families assessed for anticipation with respect to severity of hearing loss and renal involvement, the degree of hearing loss increased in four families in successive generations, but did not in the remaining three families. Generational progression in renal disease was present in three families, but in one family, the reverse was observed.

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 mutations 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

Over 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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
  • Medical genetics consultation

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 (such as vesicoureteral reflux) are present, medical and surgical treatment may prevent progression to end-stage renal disease.
    • If end-stage renal disease develops, consider renal transplantation.

Surveillance

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

Relatives at risk for BOR/BOS should be screened to determine if a treatable and/or possibly progressive otologic and/or renal abnormality is present.

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 branchiootorenal spectrum disorders have an affected parent.
  • A proband with a branchiootorenal spectrum disorder may have the disorder as the result of a de novo mutation. Approximately 10% of cases are caused by de novo mutations.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include 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 a disease-causing mutation cannot be detected in the DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband

  • Each child of an affected individual has a 50% chance of having a branchiootorenal spectrum disorder.
  • Disease severity cannot be accurately predicted and is extremely variable even within the same family.

Other family members of a proband

  • 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 are 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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 disease-causing mutation has been identified in a family member, prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

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

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.

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 about 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 disease-causing mutation 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
    1599 Hurontario Street
    Suite 201
    Mississauga Ontario L5G 4S1
    Canada
    Phone: 800-387-4474 (toll-free); 905-278-3003
    Fax: 905-271-4990
    Email: kidney@kidney.on.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
    Fax: 212-689-9261
    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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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 orthologues 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 Eya1-3 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 Eya1-, Eya2-, or Eya4-expressing cranial placodes.

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 that are described in detail in the mRNA and Protein(s) section of Entrez 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]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

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 mutations in EYA1 are not found in 60% of people with BOR/BOS, caution must be used when interpreting the effect of missense mutations 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 mutations [Kumar et al 1998], missense mutations, frameshift mutations [Kumar et al 1998], splice site mutations, 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 mutations. 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 mutations affect at least two EYA1 isoforms. In addition, the presence of mutations in exon 12 (which is skipped in the shortest transcript EYA1D) indicates that the longer isoforms are necessary for EYA1 function [Orten et al 2008]. A list of BOR-/BOS-causing mutations is maintained at www.healthcare.uiowa.edu.

Normal gene product. The proteins encoded by the transcripts EYA1A (NP_742057.1; 559 amino acids) and EYA1B (NP_742055.1; 592 amino acids) differ only in their N-terminal region. EYA1C 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.

The Eya protein has 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 missense mutations 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 Symbol.

Pathogenic allelic variants. Eight BOR-/BOS-causing SIX1 mutations have been reported [Ruf et al 2004, Ito et al 2006, Kochhar et al 2008]. One of these mutations, c.328C>T, has been seen 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 SIX1 have been shown to have abnormalities of these organs [Ando et al 2005].

Abnormal gene product. Functional characterization of several SIX1 mutations has shown that the resulting proteins mutations appear to have 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 mutations 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 Symbol.

Pathogenic allelic variants. Based on the identification of mutations in SIX5 in five of 95 unrelated patients with BOR/BOS syndrome, at least four pathogenic variants are known (see Table 4). None of these four allelic variants was observed in 150 healthy control individuals [Hoskins et al 2007].

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 mutations 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 8-15-14.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 8-15-14.

Literature Cited

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  8. Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, Kimberling WJ, Smith RJ, Weil D, Petit C, Otto EA, Xu PX, Hildebrandt F. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet. 2007;80:800–4. [PMC free article: PMC1852719] [PubMed: 17357085]
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  10. Kemperman MH, Koch SM, Joosten FB, Kumar S, Huygen PL, Cremers CW. Inner ear anomalies are frequent but nonobligatory features of the branchio-oto-renal syndrome. Arch Otolaryngol Head Neck Surg. 2002;128:1033–8. [PubMed: 12220207]
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  12. Kochhar A, Orten DJ, Sorensen JL, Fischer SM, Cremers CWRJ, Kimberling WJ, Smith RJH. SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Hum Mut. 2008;29:565. [PubMed: 18330911]
  13. Kumar S, Deffenbacher K, Marres HA, Cremers CW, Kimberling WJ. Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications. Am J Hum Genet. 2000;66:1715–20. [PMC free article: PMC1378029] [PubMed: 10762556]
  14. Kumar S, Kimberling WJ, Weston MD, Schaefer BG, Berg MA, Marres HA, Cremers CW. Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome. Hum Mutat. 1998;11:443–9. [PubMed: 9603436]
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  24. Stinckens C, Standaert L, Casselman JW, Huygen PL, Kumar S, Van de Wallen J, Cremers CW. The presence of a widened vestibular aqueduct and progressive sensorineural hearing loss in the branchio-oto-renal syndrome. A family study. Int J Pediatr Otorhinolaryngol. 2001;59:163–72. [PubMed: 11397497]
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  26. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, Tranebjarg L, Morton CC, Ryan AF, Van Camp G, Smith RJ. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet. 2001;10:195–200. [PubMed: 11159937]
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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

  • 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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