Clinical characteristics.

Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement.

Diagnosis/testing.

The clinical diagnosis of BORSD is established in an individual based on the presence of three or more major criteria OR two major criteria and two minor criteria OR one major criterion and a first-degree relative with BORSD.

The molecular diagnosis of BORSD is established in a proband with suggestive findings and a heterozygous pathogenic variant in either EYA1 or SIX1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Otologic considerations include canaloplasty to correct an atretic canal and/or excision of branchial cleft cysts/fistulae if they are infected, symptomatic, or cosmetically concerning. Audiologic considerations include hearing aids for individuals with mild-to-moderate sensorineural or mixed hearing loss and cochlear implantation (CI) for individuals with bilateral severe-to-profound hearing loss. All individuals with hearing loss should be enrolled in an appropriate educational program for the hearing impaired. CAKUT require (1) nephrologists to assess kidney function, control hypertension, manage proteinuria, and help in delaying progression of kidney disease when possible; and (2) urologists to perform corrective surgery (e.g., pyeloplasty) for UPJ obstruction and manage use of prophylactic antibiotics and/or surgical correction for VUR.

Surveillance: Routinely scheduled follow up with the treating otolaryngologist, audiologist, speech-language pathologist, nephrologist, and urologist.

Agents/circumstances to avoid: Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Individuals with CAKUT should use appropriate caution when taking medications (i.e., antibiotics and analgesics) that can impair kidney function and/or that require normal kidney physiology for their use.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic relatives at risk for BORSD to determine if treatable and/or possibly progressive otologic and/or kidney abnormalities are present. Evaluations can include molecular genetic testing if the BORSD-related genetic alteration in the family is known or comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known.

Genetic counseling.

BORSD is inherited in an autosomal dominant manner. Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of de novo EYA1 or SIX1 pathogenic variant. Each child of an individual with BORSD has a 50% chance of having BORSD. If the BORSD-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Intrafamilial variability makes it impossible to accurately predict which manifestations of BORSD may occur and how mild or severe they will be in a fetus found to have a familial BORSD-related genetic alteration.

Suggestive Findings

Branchiootorenal spectrum disorder (BORSD) should be suspected in probands with the following major and minor diagnostic criteria and family history.

Major diagnostic criteria

• Second branchial arch anomalies
  • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see Figure 1). They can extend internally to either (1) open into the tonsillar fossa or tonsillar pillars or (2) end as a blind pouch.
  • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa.
• Preauricular pits (see Figure 2) result from improper fusion of the embryonic precursors that form the structured shape of the auricle.
• Auricular malformations include lop ear, cupped ear, and anteverted pinna (see Figure 3).
• Hearing loss can be conductive, sensorineural, or mixed.
  • Severity ranges from mild to profound.
  • Hearing loss can be progressive [Chang et al 2004, Morisada et al 2014, Chen et al 2021].
• Congenital anomalies of the kidney and urinary tract (CAKUT)
  • Kidney: agenesis, hypoplasia, dysplasia
  • Urinary tract:
    • Ureteropelvic junction (UPJ) obstruction
    • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine)
    • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR)

Figure 1.

A second branchial arch fistula or sinus tract appears as a small opening in the skin on the side of the neck anterior to the sternocleidomastoid muscle (black arrow). It can extend internally to open into the tonsillar fossa or tonsillar pillars, or (more...)

Figure 2.

Preauricular pit. The pinna forms from six small prominences known as the hillocks of His. These hillocks develop around the 6th week of embryonic life from the first and second pharyngeal arches and fuse together to form the structured shape of the pinna. (more...)

Figure 3.

Anteverted pinna (posterior lateral views of left and right ear). An anteverted pinna or cupped ear is characteristic of BORSD and develops when the helix and antihelix are malformed or absent.

Minor diagnostic criteria

• Preauricular tags
• External auditory canal anomalies (atresia or stenosis)
• Middle ear anomalies
  • Malformation, malposition, dislocation, or fixation of the ossicles
  • Reduction in size or malformation of the middle ear space
• Inner ear anomalies
  • Cochlear abnormalities
    • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an EYA1 pathogenic variant [Juliano et al 2022].
    • Cochlear hypoplasia
    • Thorny apical turn of the cochlea [Pao et al 2022]
    • Enlargement of the cochlear and vestibular aqueducts
  • Enlarged vestibular aqueduct (EVA) (see Propst et al [2005])
  • Hypoplasia of the lateral semicircular canal [Ceruti et al 2002, Kemperman et al 2002]
  • Widening of the internal auditory canal [Pao et al 2022]
  • Membranous labyrinth dysplasia seen on MRI [Eliezer et al 2022]
• Other
  • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [Chang et al 2004, Morisada et al 2014, Chen et al 2021]
  • Cleft/high-arched palate

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of BORSD is established in an individual based on the presence of major and minor criteria as proposed by Chang et al [2004] (see Suggestive Findings):

• Three or more major criteria
  OR
• Two major criteria and two minor criteria
  OR
• One major criterion and a first-degree relative with BORSD

The molecular diagnosis of BORSD is established in the absence of complete clinical criteria [Masuda et al 2022] in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) variant in either EYA1 or SIX1 (~90% of affected individuals) [Cho et al 2024]
• A heterozygous copy number abnormality (most commonly deletion) or structural variant of 8q13.2-13.3 involving EYA1 (10% of affected individuals) [Sanchez-Valle et al 2010, Brophy et al 2013, Cho et al 2024]
  Note: Copy number abnormalities involving SIX1 have not been reported in BORSD to date. A complex chromosomal rearrangement that includes a duplication of chromosome 14q22.3-q23.3 (including SIX1) and a deletion of 13q21.31-q21.32 has been reported in an individual with overlapping features of branchiootorenal syndrome (BORS) and oculoauriculovertebral spectrum (OAVS) [Ou et al 2008].

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous EYA1 or SIX1 variant of uncertain significance does not establish or rule out the diagnosis. (3) Variants in SIX5 (previously implicated in the pathogenesis of BORSD) are not currently considered a cause of BORSD (see Molecular Pathogenesis).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel, chromosomal microarray) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement.

Extreme variability can be observed in the presence, severity, and type of branchial arch and otologic anomalies and CAKUT between the right and left sides of an affected individual. Similarly, marked interfamilial variability and intrafamilial variability are observed.

To date, more than 400 individuals with BORSD have been described in the literature [Chang et al 2004, Morisada et al 2014, Chen et al 2021]. The following description of the phenotypic features associated with BORSD is based on these reports.

Otologic findings, the most consistent feature of BORSD reported in more than 90% of individuals, include the following [Chang et al 2004, Chen et al 2021].

• Hearing loss (>90%)
  • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%)
  • Severity: mild (27%), moderate (22%), severe (33%), profound (16%)
  • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [Kemperman et al 2004]. Although progressive hearing loss typically begins during childhood or adolescence, the age of onset has significant intrafamilial variability and interfamilial variability [Chen et al 2021].
• Abnormalities of the pinnae include preauricular pits (82%), lop ear malformation (36%), and preauricular tags (13%). Preauricular pits might require further evaluation if intermittent infection is occurring; definitive treatment is surgical excision.
• Second branchial arch anomalies, present in approximately 50% of affected individuals, include branchial cleft cysts or sinus tracts that may require excision if they are infected, symptomatic (i.e., draining), or cosmetically concerning [Chang et al 2004, Chen et al 2021].
• Abnormalities of the external auditory canal include atresia or stenosis (29%). Canaloplasty might be required to correct an atretic canal.

Congenital anomalies of the kidney and urinary tract (CAKUT), present in 67% of individuals, include the following [Chang et al 2004, Morisada et al 2014, Chen et al 2021]:

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

CAKUT can be unilateral or bilateral and can occur in any combination.

The most severe anomalies (i.e., bilateral renal agenesis) result in pregnancy loss (due to miscarriage) or neonatal death.

The less severe findings – that are nonetheless medically significant – can result in progressive kidney dysfunction and may lead to ESKD.

Focal segmental glomerulosclerosis (FSGS). Findings of FSGS [Saiki et al 2022, Lin et al 2023] support the earlier findings of Ruf et al [2004] and Brophy et al [2013] that proteinuria, hematuria, and glomerulosclerosis, reported in some individuals, may contribute to the risk of ESKD independent of that associated with CAKUT.

If kidney function is sufficiently impaired, kidney replacement therapy (KRT) may be required. KRT refers to medical treatments that substitute for the normal kidney function and includes dialysis (hemodialysis and peritoneal dialysis) and kidney transplantation (see Treatment of Manifestations).

Other findings

• Lacrimal duct aplasia (absence or hypoplasia of the lacrimal ducts) presents as epiphora due to absence or hypoplasia of the nasolacrimal or tear duct, a tiny tube that carries tears from the eye to the nose [Chang et al 2004].
• Short or cleft palate may contribute to feeding or speech difficulties [Morisada et al 2014].
• Retrognathia (posteriorly positioned mandible) may contribute to airway or feeding difficulties [Rickard et al 2001].
• Facial nerve paralysis (inability to move one side of the face) may occasionally be seen [Kochhar et al 2008].
• Facial asymmetry is often mild and may involve mandibular hypoplasia or hemifacial microsomia, which may contribute to feeding or speech difficulties in infancy and childhood [Chang et al 2004, Morisada et al 2014, Chen et al 2021].
• Gustatory lacrimation (also known as "crocodile tears"), involuntary tearing while eating or drinking, is occasionally seen.
• Congenital anterior segment anomalies of the eye with or without cataract have been reported in two individuals with other features of BORSD, suggesting that congenital eye anomalies may be an occasional feature of BORSD [Azuma et al 2000] (see Genetically Related Disorders).
• Euthyroid goiter, enlargement of the thyroid gland associated with normal levels of thyroid hormone, has been reported.

Intrafamilial variability. Families segregating heterozygous pathogenic variants exhibit broad intrafamilial variability [Cho et al 2024] (full text). For example, in one large family, all 18 persons heterozygous for a SIX1 pathogenic variant had hearing loss; however, only six persons also had ear pits, three others had branchial cysts, and two developed renal carcinoma [Ruf et al 2004]. Note: The finding of renal carcinoma has not otherwise been described in BORSD; thus, any possible association of renal tumors with BORSD requires more data.

In a small Tunisian family, five persons heterozygous for a SIX1 pathogenic variant had moderate-to-profound mixed or sensorineural hearing loss. Although preauricular pits were present in four persons, none had other second branchial arch anomalies or anomalies of the temporal bone, or renal abnormalities [Mosrati et al 2011].

Genotype-Phenotype Correlations

Clinically actionable genotype-phenotype correlations for EYA1 and SIX1 are limited, as both genes exhibit high interfamilial variability and intrafamilial variability, sometimes even for the same pathogenic variant [Cho et al 2024]. However, the following correlations with the involved gene have been observed:

• EYA1 pathogenic variants are associated with the specific "unwound cochlea" cochlear malformation or offset cochlear turns (measurable by turn angle ratio [TAR] on CT or MRI; TAR <0.476), which are seen in 100% of individuals with an EYA1 pathogenic variant and is considered diagnostic for EYA1-related BORSD [Juliano et al 2022].
• SIX1 pathogenic variants are always associated with hearing loss, which can be sensorineural or mixed [Lee et al 2023].

Penetrance

Based on clinical studies of large pedigrees, BORSD appears to have 100% penetrance; however, intrafamilial variability and interfamilial variability are high [Chang et al 2004, Chen et al 2021, Cho et al 2024].

Nomenclature

Branchiootorenal spectrum disorder (BORSD) encompasses branchiootorenal syndrome (BORS) and branchiootic syndrome (BOS), which differ primarily by the presence (BORS) or absence (BOS) of renal abnormalities. Individuals with a confirmed molecular diagnosis within the same family often exhibit features consistent with either BORS or BOS, highlighting the intrafamilial variability in phenotypic expression [Orten et al 2008]. Accordingly, the term "branchiootorenal spectrum disorder" is preferred as it captures the full phenotypic continuum more accurately than the older descriptive phenotype designations.

BORS was originally known eponymously as Melnick-Fraser syndrome.

Prevalence

Large-scale prevalence data for BORSD are lacking. In the authors' experience at the Molecular Otolaryngology and Renal Research Laboratories (MORL), as of January 2025, 3,376 of 8,032 persons (42%) screened for genetic causes of hearing loss (no exclusionary criteria) had an identified genetic cause of hearing loss. Of persons with a genetic diagnosis, 58 persons (0.72%) had BORSD [H Azaiez & R Smith, unpublished data].

A comprehensive nationwide survey in Japan estimated that only 250 individuals with BORSD (95% confidence interval: 170-320) were identified in clinics in 2009-2010, suggesting that the prevalence of BORSD is lower in Japan than in Western countries [Morisada et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BORSD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care ideally involves coordinated care by a multidisciplinary team including an otolaryngologist, audiologist, speech-language pathologist, nephrologist, urologist, clinical geneticist, and genetic counselor (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

Agents/Circumstances to Avoid

Hearing loss. Individuals with hearing loss should avoid environmental exposures known to cause hearing loss.

Most important for persons with mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises, particularly secondary to earbud use. The headphone safety feature built into most smartphones can be set to a maximum limit of 75 decibels (dB).

Headphone/earbud safety features can be found in the phone settings menu:

• In iPhones, under Settings > Sounds & Haptics > Headphone Safety
• In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit

Also see these general resources on noise reduction:

• 6 Simple Ways to Check If Your Headphones Are Too Loud
• How Do I Prevent Hearing Loss from Loud Noise?

Anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing has led some providers to recommend avoiding activities such as weightlifting and contact sports [Forli et al 2021]; however, evidence is insufficient to support the claim that avoiding these activities will decrease the risk of overall hearing loss progression [Brodsky & Choi 2018]. While it is appropriate for health care providers to alert families to the possible association between EVA and hearing loss following head injuries, families should be encouraged to make their own decisions on participation in contact sports while taking into account the findings of Brodsky & Choi [2018].

Kidney involvement. Individuals with CAKUT should use appropriate caution when taking medications (i.e., antibiotics and analgesics) that can impair kidney function and/or that require normal kidney physiology for their use.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic relatives at risk for BORSD to determine if treatable and/or possibly progressive otologic and/or kidney abnormalities are present. Evaluations can include:

• Molecular genetic testing if the BORSD-related genetic alteration in the family is known;
• Comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [Chang et al 2004].

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

Pregnancy Management

A pregnant woman with BORSD who has known kidney involvement should consider seeking care from a maternal-fetal medicine specialist. These specialists have additional training and board certification in managing pregnancies with complex medical problems.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Branchiootorenal spectrum disorder (BORSD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• An individual diagnosed with BORSD may represent a simplex case (i.e., the only affected family member). Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of de novo EYA1 or SIX1 pathogenic variant [Klimara et al 2022, Cho et al 2024].
• If the proband appears to be the only affected family member, evaluation of the parents of the proband is recommended to determine their clinical/genetic status and inform recurrence risk assessment. Evaluations include the following:
  • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: the proband has a de novo pathogenic variant; or the proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    Note: If the proband has a copy number variant or complex structural rearrangement involving EYA1, genomic testing capable of detecting the genetic alteration identified in the proband is recommended (see Molecular Pathogenesis, EYA-specific laboratory technical considerations).
  • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband.
• Although most individuals diagnosed with BORSD have an affected parent, the proband may appear to be the only affected family member because of failure to recognize the disorder in relatives. Therefore, appropriate evaluation of the parents (i.e., molecular genetic testing if the proband has a molecular diagnosis and/or clinical evaluation of the parents) is necessary to establish the family history.

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents:

• If a parent has a clinical and/or molecular diagnosis of BORSD, the risk to the sibs is 50%. BOSRD appears to have 100% penetrance; however phenotypic expressivity is highly variable. Disease phenotype and severity in affected sibs cannot be accurately predicted and is extremely variable even within the same family. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [Chang et al 2004].
• If a molecular diagnosis has been established in the proband and the BORSD-related genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Miyagawa et al 2015].
• If the proband represents a simplex case and the parents are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with BORSD has a 50% chance of having BORSD.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If the BORSD-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Intrafamilial variability makes it impossible to accurately predict which manifestations of BORSD may occur and how mild or severe they will be in a fetus found to have a familial BORSD-related genetic alteration.

Fetal ultrasound examination. For fetuses at increased risk for BORSD, prenatal ultrasound examination at 16-17 weeks' gestation can be considered for evaluation of significant kidney 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

EYA1 and SIX1 encode proteins that form part of a tightly regulated transcriptional complex essential for organ development, particularly the ear, kidneys, and branchial arches. Disruption of this complex leads to abnormal morphogenesis, cell proliferation, and cellular fate specification [Li et al 2003].

EYA1 encodes a dual-function transcriptional coactivator and tyrosine phosphatase expressed in the developing otic placode, branchial arches, and the metanephric mesenchyme of the kidney [Kalatzis & Petit 2000, Li et al 2003].

SIX1 encodes a homeobox-containing transcription factor that functions as a DNA-binding partner for EYA1.

SIX5. Although SIX5 was initially proposed as a causative gene of BORSD, subsequent studies have failed to confirm a definitive pathogenic role [Krug et al 2011]. Additionally, functional studies have shown that mice with a targeted deletion of Six5 develop cataracts but do not exhibit otologic or renal phenotypes consistent with BORSD [Klesert et al 2000, Sarkar et al 2000]. These findings contrast sharply with the phenotypes seen in mice with targeted deletions of Eya1 and Six1 that recapitulate key features observed in BORSD.

The ClinGen Hearing Loss Gene Curation Expert Panel has classified the association between SIX5 and BORSD as "Disputed," citing insufficient genetic and functional evidence. Therefore, SIX5 is no longer considered an associated gene in BORSD.

• See ClinGen Hearing Loss GCEP status.
• See Hereditary Hearing Loss Homepage.

Mechanism of disease causation

• EYA1. Loss of function
• SIX1. Loss of function

EYA-specific laboratory technical considerations.

• Copy number abnormalities and structural variants. EYA1 is known for a high frequency of copy number variants (CNVs) (including most commonly multiexon or whole-gene deletions) and structural variants such as complex genomic rearrangements, inversions, and Alu element insertions that may not be detected using routine sequencing technologies (e.g., Sanger sequencing) or standard next-generation sequencing methods including multigene panels and exome sequencing. Therefore, consideration of optimal methods for the detection of these variants is recommended to ensure diagnostic sensitivity including gene-targeted deletion/duplication analysis methods such as multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray (CMA), custom CNV analysis tools, and whole-genome sequencing [Chang et al 2004, Orten et al 2008, Krug et al 2011, Brophy et al 2013, Zheng et al 2021, Cho et al 2024].
• Balanced chromosomal rearrangements involving the 8q13.3 region including pericentric inversions of chromosome 8 have been detected but may elude detection using some of the above methods and may require high-resolution karyotyping and/or fluorescent in situ hybridization (FISH) [Schmidt et al 2014].

Author Notes

Richard JH Smith, MD, is a pediatric otolaryngologist, human geneticist, and complementologist at the University of Iowa. He directs the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offers comprehensive genetic testing for hearing loss. He is interested in collaborating with clinicians treating families affected by genetic hearing loss in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. He is actively involved in research in individuals with a phenotype suggestive of branchiootorenal spectrum disorder (BORSD). For questions about hearing loss and the diagnosis of BORSD, email ude.awoiu@lrom. Lab website: morl.lab.uiowa.edu

Hela Azaiez, MS, PhD, is a human geneticist specializing in the molecular genetics and genomics of hearing loss in the Department of Medical and Molecular Genetics at Indiana University School of Medicine. She is actively engaged in basic and translational research, with a focus on the genetic etiology of hearing loss. Her research aims to decode the molecular mechanisms of hearing and deafness, intending to translate this knowledge into improved clinical diagnostics and enhanced patient care. She also maintains a keen interest in collaborating with clinicians who treat families affected by genetic hearing loss, including BORSD.

Acknowledgments

Supported in part by grants DC02842, DC012049, and DC017955 from the NIDCD (RJHS).

Author History

Hela Azaiez, MS, PhD (2025-present)
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

• 26 June 2025 (bp) Comprehensive update posted live
• 6 September 2018 (ha) Comprehensive update posted live
• 22 October 2015 (me) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 27 August 2009 (me) Comprehensive update posted live
• 24 January 2006 (me) Comprehensive update posted live
• 30 October 2003 (me) Comprehensive update posted live
• 28 November 2001 (me) Comprehensive update posted live
• 19 March 1999 (pb) Review posted live
• 6 January 1999 (rjhs) Original submission

Published Guidelines / Consensus Statements

• 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 6-16-25.
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 6-16-25.

Literature Cited

• Arai H, Noguchi A, Shina K, Otaka S, Takahashi I, Kosaki K, Takahashi T. A child with branchio-oto-renal spectrum disorder carrying an SIX1 variant. Pediatr Int. 2023;65:e15638. [PubMed: 37795857]
• Azuma N, Hirakiyama A, Inoue T, Asaka A, Yamada M. Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Hum Mol Genet. 2000;9:363–6. [PubMed: 10655545]
• Biggs K, Crundwell G, Metcalfe C, Muzaffar J, Monksfield P, Bance M. Anatomical and audiological considerations in branchiootorenal syndrome: a systematic review. Laryngoscope Investig Otolaryngol. 2022;7:540-63. [PMC free article: PMC9008175] [PubMed: 35434312]
• Brodsky JR, Choi SS. Should children with an enlarged vestibular aqueduct be restricted from playing contact sports? Laryngoscope. 2018;128:2219-20. [PubMed: 29481706]
• Brophy PD, Alasti F, Darbro B, Clarke J, Nishimura C, Smith RJ, Manak JR. Genome-wide copy number variation analysis of a branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes. Hum Genet. 2013;132:1339–50. [PMC free article: PMC3830662] [PubMed: 23851940]
• Ceruti S, Stinckens C, Cremers CW, Casselman JW. Temporal bone anomalies in the branchio-oto-renal syndrome: detailed computed tomographic and magnetic resonance imaging findings. Otol Neurotol. 2002;23:200–7. [PubMed: 11875350]
• Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat. 2004;23:582–9. [PubMed: 15146463]
• Chen A, Song J, Acke FRE, Mei L, Cai X, Feng Y, He C. Otological manifestations in branchiootorenal spectrum disorder: a systematic review and meta-analysis. Clin Genet. 2021;100:3-13. [PubMed: 33624842]
• Chen X, Wang J, Mitchell E, Guo J, Wang L, Zhang Y, Hodge JC, Shen Y. Recurrent 8q13.2-13.3 microdeletions associated with branchio-oto-renal syndrome are mediated by human endogenous retroviral (HERV) sequence blocks. BMC Med Genet. 2014;15:90. [PMC free article: PMC4152767] [PubMed: 25135225]
• Cho SH, Jeong SH, Choi WH, Lee SY. Genomic landscape of branchio-oto-renal syndrome through whole-genome sequencing: a single rare disease center experience in South Korea. Int J Mol Sci. 2024;25. [PMC free article: PMC11311636] [PubMed: 39125727]
• Eliezer M, Mamelle E, Hautefort C. Membranous labyrinth dysplasia in branchio-oto-renal syndrome. Otol Neurotol. 2022;43:e861-e863. [PubMed: 35970162]
• Estefanía E, Ramírez-Camacho R, Gomar M, Trinidad A, Arellano B, García-Berrocal JR, Verdaguer JM, Vilches C. Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome. Ann Hum Genet. 2006;70:140–4. [PubMed: 16441263]
• Forli F, Lazzerini F, Auletta G, Bruschini L, Berrettini S. Enlarged vestibular aqueduct and Mondini Malformation: audiological, clinical, radiologic and genetic features. Eur Arch Otorhinolaryngol. 2021;278:2305-12. [PMC free article: PMC8165072] [PubMed: 32910226]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Juliano AF, D'Arco F, Pao J, Picariello S, Clement E, Moonis G, Robson CD. The cochlea in branchio-oto-renal syndrome: an objective method for the diagnosis of offset cochlear turns. AJNR Am J Neuroradiol. 2022;43:1646-52. [PMC free article: PMC9731253] [PubMed: 36175083]
• Kalatzis V, Petit C. Branchio-oto-renal syndrome. Adv Otorhinolaryngol. 2000;56:39-44. [PubMed: 10868212]
• 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]
• Kemperman MH, Koch SM, Kumar S, Huygen PL, Joosten FB, Cremers CW. Evidence of progression and fluctuation of hearing impairment in branchio-oto-renal syndrome. Int J Audiol. 2004;43:523–32. [PubMed: 15726843]
• Klimara MJ, Nishimura C, Wang D, Kolbe DL, Schaefer AM, Walls WD, Frees KL, Smith RJH, Azaiez H. De novo variants are a common cause of genetic hearing loss. Genet Med. 2022;24:2555-67. [PMC free article: PMC9729384] [PubMed: 36194208]
• Klesert TR, Cho DH, Clark JI, Maylie J, Adelman J, Snider L, Yuen EC, Soriano P, Tapscott SJ. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet. 2000;25:105-9. [PubMed: 10802667]
• 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 Mutat. 2008;29:565. [PubMed: 18330911]
• Krug P, Moriniere V, Marlin S, Koubi V, Gabriel HD, Colin E, Bonneau D, Salomon R, Antignac C, Heidet L. Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. Hum Mutat. 2011;32:183–90. [PubMed: 21280147]
• Lee S, Yun Y, Cha JH, Han JH, Lee DH, Song JJ, Park MK, Lee JH, Oh SH, Choi BY, Lee SY. Phenotypic and molecular basis of SIX1 variants linked to non-syndromic deafness and atypical branchio-otic syndrome in South Korea. Sci Rep. 2023;13:11776. [PMC free article: PMC10361970] [PubMed: 37479820]
• Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247–54. [PubMed: 14628042]
• Lin Z, Li J, Pei Y, Mo Y, Jiang X, Chen L. Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases. BMC Nephrol. 2023;24:248. [PMC free article: PMC10464405] [PubMed: 37612603]
• Masuda M, Kanno A, Nara K, Mutai H, Morisada N, Iijima K, Morimoto N, Nakano A, Sugiuchi T, Okamoto Y, Masuda S, Katsunuma S, Ogawa K, Matsunaga T. Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome. Sci Rep. 2022;12:969. [PMC free article: PMC8770796] [PubMed: 35046468]
• Miyagawa M, Nishio SY, Hattori M, Takumi Y, Usami S. Germinal mosaicism in a family with BO syndrome. Ann Otol Rhinol Laryngol. 2015;124 Suppl 1:118S-22S. [PubMed: 25780253]
• Morisada N, Nozu K, Iijima K. Branchio-oto-renal syndrome: comprehensive review based on nationwide surveillance in Japan. Pediatr Int. 2014;56:309–14. [PubMed: 24730701]
• Mosrati MA, Hammami B, Rebeh IB, Ayadi L, Dhouib L, Ben Mahfoudh K, Hakim B, Charfeddine I, Mnif J, Ghorbel A, Masmoudi S. A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. Eur J Med Genet. 2011;54:e484–8. [PubMed: 21700001]
• Orten DJ, Fischer SM, Sorensen JL, Radhakrishna U, Cremers CW, Marres HA, Van Camp G, Welch KO, Smith RJ, Kimberling WJ. Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Hum Mutat. 2008;29:537–44. [PubMed: 18220287]
• Ou Z, Martin DM, Bedoyan JK, Cooper ML, Chinault AC, Stankiewicz P, Cheung SW. Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement. Am J Med Genet A. 2008;146A:2480-9. [PubMed: 18666230]
• Pao J, D'Arco F, Clement E, Picariello S, Moonis G, Robson CD, Juliano AF. Re-examining the cochlea in branchio-oto-renal syndrome: genotype-phenotype correlation. AJNR Am J Neuroradiol. 2022;43:309-14. [PMC free article: PMC8985666] [PubMed: 35058298]
• Propst EJ, Blaser S, Gordon KA, Harrison RV, Papsin BC. Temporal bone findings on computed tomography imaging in branchio-oto-renal syndrome. Laryngoscope. 2005;115:1855-62. [PubMed: 16222209]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rickard S, Parker M, van't Hoff W, Barnicoat A, Russell-Eggitt I, Winter RM, Bitner-Glindzicz M. Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM. Hum Genet. 2001;108:398–403. [PubMed: 11409867]
• Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004;101:8090–5. [PMC free article: PMC419562] [PubMed: 15141091]
• Saiki R, Katayama K, Kitano M, Tsujimoto K, Tanaka F, Suzuki Y, Murata T, Kurita T, Okamoto R, Takeuchi K, Dohi K. A perihilar variant of focal segmental glomerulosclerosis due to de novo branchio-oto-renal syndrome. Intern Med. 2022;61:2033-8. [PMC free article: PMC9334246] [PubMed: 34866102]
• Salam AA, Häfner FM, Linder TE, Spillmann T, Schinzel AA, Leal SM. A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21eq22 in a Swiss German kindred. Am J Hum Genet. 2000;66:1984–8. [PMC free article: PMC1378045] [PubMed: 10777717]
• Sanchez-Valle A, Wang X, Potocki L, Xia Z, Kang SH, Carlin ME, Michel D, Williams P, Cabrera-Meza G, Brundage EK, Eifert AL, Stankiewicz P, Cheung SW, Lalani SR. HERV-mediated genomic rearrangement of epsilon YA1 in an individual with branchio-oto-renal syndrome. Am J Med Genet A. 2010;152A:2854–60. [PMC free article: PMC3605882] [PubMed: 20979191]
• Sarkar PS, Appukuttan B, Han J, Ito Y, Ai C, Tsai W, Chai Y, Stout JT, Reddy S. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nat Genet. 2000;25:110-4. [PubMed: 10802668]
• Schmidt T, Bierhals T, Kortüm F, Bartels I, Liehr T, Burfeind P, Shoukier M, Frank V, Bergmann C, Kutsche K. Branchio-otic syndrome caused by a genomic rearrangement: clinical findings and molecular cytogenetic studies in a patient with a pericentric inversion of chromosome 8. Cytogenet Genome Res. 2014;142:1-6. [PubMed: 24135068]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• 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]
• Vervoort VS, Smith RJ, O'Brien J, Schroer R, Abbott A, Stevenson RE, Schwartz CE. Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome. Eur J Hum Genet. 2002;10:757-66. [PubMed: 12404110]
• Zheng H, Xu J, Wang Y, Lin Y, Hu Q, Li X, Chu J, Sun C, Chai Y, Pang X. Identification and characterization of a cryptic genomic deletion-insertion in EYA1 associated with branchio-otic syndrome. Neural Plast. 2021;2021:5524381. [PMC free article: PMC8046558] [PubMed: 33880118]