Clinical characteristics.

SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL), characterized by inner ear malformations also associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic SLC26A4-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs). The time of onset and type of presentation of the SNHL vary (such that some newborns pass their newborn hearing screening); however, by age three years most children have bilateral and severe-to-profound hearing loss. Manifestations of vestibular dysfunction (such as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well) can precede or accompany the fluctuations in hearing typical of this disorder. Thyroid enlargement (goiter) occurs gradually and is typically evident in the second decade, especially if iodine is not routinely included in the diet.

Diagnosis/testing.

The diagnosis of SLC26A4-SNHL is established in a proband with suggestive findings and biallelic pathogenic variants in SLC26A4 identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive treatment includes multidisciplinary care by specialists in hearing habilitation, as early auditory intervention is critical to the development of speech and language. Habilitation options tailored to the degree and frequency of hearing loss can include hearing aids when hearing loss is mild to severe and consideration of cochlear implantation (CI) when hearing aids have had limited benefit. When considering CI, it is essential that the treating otolaryngologist be aware of the possible perioperative complications (most commonly perilymph gusher/oozing) and postoperative complications (most commonly transient vertigo) in individuals with SLC26A4-SNHL. Educational and early intervention programs designed for individuals with hearing loss are recommended. Medical treatment of thyroid enlargement and/or abnormal thyroid function requires consultation with an endocrinologist.

Surveillance: Audiometric testing every three to six months until age three years and annually thereafter; baseline ultrasound to assess thyroid size at age ten years, followed by repeat ultrasound every five to ten years based on findings on palpation of thyroid size.

Agents/circumstances to avoid: Follow standard recommendations for individuals with hearing loss. Despite anecdotal reports that head injuries resulting in increased intracranial pressure in individuals with enlarged vestibular aqueduct can occasionally trigger a decline in hearing, evidence is insufficient to support that avoidance of these activities decreases the overall risk of progression of hearing loss. While health care providers should alert families to this possible association, it is recommended that families be encouraged to make their own decisions on participation in contact sports.

Evaluation of at-risk sibs: It is appropriate to determine the genetic status of at-risk sibs of a proband with SLC26A4-SNHL (i.e., a proband with known biallelic SLC26A4 pathogenic variants) shortly after birth so that appropriate and early support and management can be provided to the child and family.

Genetic counseling.

SLC26A4-SNHL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A4 pathogenic variant, each sib of the proband has at conception a 25% chance of having SLC26A4-SNHL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the pathogenic variants. Once biallelic SLC26A4 pathogenic variants have been identified in the proband, heterozygote testing for relatives of an individual with SLC26A4-SNHL and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

SLC26A4-SNHL should be considered in probands with the following clinical findings of sensorineural hearing loss, inner ear malformations, vestibular dysfunction, and thyroid abnormalities and family history [Honda & Griffith 2022].

Clinical findings

• Sensorineural hearing loss (SNHL)
  • Onset varies (congenital, prelingual, postlingual).
  • Newborn hearing screening can be normal.
  • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [Mey et al 2019].
  • Fluctuating or progressive SNHL can occur.
  • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [Merchant et al 2007].
• Inner ear malformations detected by CT or MRI
  • Bilateral enlargement of the vestibular aqueduct * (EVA). The vestibular aqueduct, the bony canal that surrounds the endolymphatic duct and part of the endolymphatic sac, is abnormally dilated in all individuals. EVA is defined as a midpoint diameter of the endolymphatic duct ≥1.0 mm or diameter of the operculum ≥2.0 mm [Boston et al 2007, Vijayasekaran et al 2007, Chattaraj et al 2013] (see Figure 1).
  • Incomplete cochlear partition type II * (IP-II), observed in 22%-74% of individuals, is an undersegmentation anomaly of the cochlea with specific imaging and histologic findings. Deficient partitioning of the upper turns of the cochlea (the cochlea usually has 2½ turns) results in a cochlea with 1½ turns and a cystic apex or "scala communis" [D'Arco et al 2024].
    * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad."
  • Cochlear modiolar hypoplasia or deficiency, which is also common, can be detected by CT or MRI.
  • Note: A radiologic diagnosis of EVA with or without cochlear hypoplasia is not specific to SLC26A4-SNHL (see Differential Diagnosis for other causes of these temporal bone malformations).
• Vestibular dysfunction (4%-47% of individuals)
  • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting.
  • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [Zalewski et al 2015].
  • Note: There is no correlation between the severity of hearing loss and clinical signs and symptoms of vestibular dysfunction or objective evidence of vestibular dysfunction.
• Thyroid findings of Pendred syndrome
  • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [Madeo et al 2009, Honda & Griffith 2022] (see Management).
    * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [Madeo et al 2009, Honda & Griffith 2022]. Click here (pdf) for details of the perchlorate discharge test.
  • Euthyroid goiter is incompletely penetrant [Honda & Griffith 2022]. Goiter generally becomes apparent after age ten years if iodine is not routinely included in the diet; it is rarely observed in countries with universal salt iodization programs.
  • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [Madeo et al 2009].
  • Note: Consensus clinical diagnostic criteria for Pendred syndrome (used in the past before the availability of molecular genetic testing) included the presence of sensorineural hearing loss, enlarged vestibular aqueduct (EVA) with or without cochlear and vestibular malformations, and an iodide organification defect that may or may not lead to goiter.

Figure 1.

Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SLC26A4-SNHL is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC26A4 identified by molecular genetic testing (see Table 1).

Note: The diagnosis of SLC26A4-SNHL cannot be made when only a single SLC26A4 pathogenic variant is identified (for more details see Molecular Genetics, Other molecular mechanisms under investigation.

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 biallelic SLC26A4 variants of uncertain significance (or of one known SLC26A4 pathogenic variant and one SLC26A4 variant of uncertain significance) does not establish or rule out the diagnosis. (3) If only a single SLC26A4 pathogenic variant is identified, the possibility of intragenic deletions or duplications should be considered [RJH Smith, personal observation].

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

Note: Single-gene testing (sequence analysis of SLC26A4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene hearing loss panel that includes SLC26A4 and other genes of interest that cause sensorineural hearing loss (see Differential Diagnosis) while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, more than 600 pathogenic variants have been reported in SLC26A4 [Azaiez et al 2018], most of which are single-nucleotide variants (e.g., missense, nonsense) or small deletion/duplications that impact the coding regions and the intronic regions closely flanking the exons (i.e., splice sites) and thus are likely to be identified on exome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL), characterized by inner ear malformations associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic SLC26A4-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs).

The considerable intrafamilial variability (i.e., variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family) in temporal bone anomalies, hearing loss, and thyroid disease makes the distinction between nonsyndromic SLC26A4-SNHL and PDS during childhood difficult [Reardon et al 1999, Tsukamoto et al 2003, Napiontek et al 2004, Goldfeld et al 2005, Madeo et al 2009, Mey et al 2019].

Hundreds of individuals have been identified with biallelic SLC26A4 pathogenic variants. The following description of the phenotypic features associated with SLC26A4-SNHL is based on data from more than 300 affected persons [Azaiez et al 2007, Aimoni et al 2017, Mey et al 2019, Forli et al 2021, Smits et al 2022, D'Arco et al 2024].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified in individuals with biallelic SLC26A4 pathogenic variants.

Nomenclature

Nonsyndromic SLC26A4-SNHL is also referred to as DFNB4 (autosomal recessive nonsyndromic deafness 4), nonsyndromic enlargement of the vestibular aqueduct (NSEVA), and DFNB4/NSEVA.

Pendred syndrome is also referred to as "autosomal recessive sensorineural hearing loss, enlarged vestibular aqueduct, and goiter."

EVA is also referred to as dilation of the vestibular aqueduct (DVA).

Large vestibular aqueduct syndrome (LVAS) or enlarged vestibular aqueduct syndrome (EVAS) refers to EVA-related hearing loss and includes EVA-related hearing loss of unknown cause, nonsyndromic SLC26A4-SNHL, and Pendred syndrome [Honda & Griffith 2022].

Prevalence

EVA is the most common radiologic malformation of the inner ear associated with SNHL [Valvassori & Clemis 1978]; when nonsyndromic SLC26A4-SNHL and PDS are considered part of the same disease spectrum, biallelic SLC26A4 pathogenic variants are the third most frequent cause of hearing loss (see Figure 2). See also Genetic Hearing Loss Overview.

Figure 2.

In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic SLC26A4 pathogenic variants was the third most common (more...)

For studies of the SLC26A4 mutational spectrum and ethnicity-specific differences in the prevalence of pathogenic variants, see Tsukada et al [2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SLC26A4-SNHL, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

• Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry)
• Assessment of vestibular function during early childhood (should be considered)
• Thyroid ultrasonography and thyroid function tests (T₃ [triiodothyronine], T₄ [thyroxine], and TSH [thyroid-stimulating hormone]) during early childhood with endocrinologist consultation as needed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of SLC26A4-SNHL to facilitate medical and personal decision making
• Assessment of need for family support and resources including community or online resources and social work involvement for parental support

See also Genetic Hearing Loss Overview.

Treatment of Manifestations

There is no cure for SLC26A4-SNHL.

For general information on management of hearing loss in children and adults, see Genetic Hearing Loss Overview, Management.

Hearing habilitation. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss.

• Hearing aids may be used in persons with mild-to-severe hearing loss.
• Cochlear implantation (CI), which provides good hearing habilitation in individuals with SLC26A4-SNHL, should be considered if hearing aids have provided only limited benefit. As hearing loss fluctuates and gradually progresses, children with SLC26A4-SNHL receive implants later than children with other types of nonsyndromic hearing loss [Mey et al 2020]. Indeed, a systematic review found the average age at CI was 60 months for children with SLC26A4-SNHL as compared to 12 months or younger for children with other types of severe-to-profound nonsyndromic hearing loss [Hansen et al 2023].
• CI in individuals with SLC26A4-SNHL is associated with a higher risk of perioperative complications (most commonly perilymph gusher/oozing) and postoperative complications (most commonly transient vertigo). Therefore, preoperative vestibular testing should be considered to (1) inform the otolaryngologist regarding the abnormal vestibular anatomy and (2) anticipate possible vestibular dysfunction following CI [Hansen et al 2023].

Educational and early intervention programs designed for individuals with hearing loss are recommended (see Genetic Hearing Loss Overview, Management).

Medical treatment of thyroid enlargement and/or abnormal thyroid function requires consultation with an endocrinologist.

Surveillance

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

Hearing loss

• The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [Hansen et al 2023].
• Repeat audiometric testing every three to six months until age three years and annually thereafter.

Thyroid function

• Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [Madeo et al 2009]).
• While tests of thyroid function are usually normal in individuals with SLC26A4-SNHL irrespective of thyroid size, this testing is important in the evaluation and management of signs and symptoms of hypo- and hyperthyroidism and should be considered when the medical history and/or physical examination suggest thyroid dysfunction [Madeo et al 2009].

Agents/Circumstances to Avoid

See Genetic Hearing Loss Overview, Agents/Circumstances to Avoid.

There are anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, leading some providers to recommend avoiding activities like 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 health care providers should 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, taking into account that head trauma may not significantly affect the overall risk of hearing loss progression [Brodsky & Choi 2018].

Evaluation of Sibs at Risk

It is appropriate to determine the genetic status of at-risk sibs of a proband with SLC26A4-SNHL (i.e., a proband with known biallelic SLC26A4 pathogenic variants) shortly after birth so that appropriate and early support and management can be provided to the child and family. Sibs found to have biallelic SLC26A4 pathogenic variants should be evaluated for hearing loss, vestibular dysfunction, and abnormal thyroid function (see Evaluations Following Initial Diagnosis).

Note: As individuals with nonsyndromic enlarged vestibular aqueduct can have normal hearing at birth only to develop progressive hearing loss during early childhood, a normal newborn hearing screening does not rule out the possibility that an at-risk sib has SLC26A4-SNHL.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL) is inherited in an autosomal recessive manner.

Note: Although digenic inheritance of hearing loss with enlarged vestibular aqueduct has been described involving pathogenic variants in SLC26A4 in trans with pathogenic variants in EPHA2 [Li et al 2020], FOXI1 [Yang et al 2007], or KCNJ10 [Yang et al 2009], more recent studies have not supported this pattern of inheritance [Smits et al 2022].

Risk to Family Members (Proband with Biallelic SLC26A4 Pathogenic Variants)

Parents of a proband

• The parents of a child with biallelic SLC26A4 pathogenic variants are presumed to be heterozygous for an SLC26A4 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC26A4 pathogenic variant and to allow reliable recurrence assessment.
• If an SLC26A4 pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes do not develop SLC26A4-SNHL.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC26A4 pathogenic variant, each sib of the proband has at conception a 25% chance of having SLC26A4-SNHL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the SLC26A4 pathogenic variants.
• Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with SLC26A4-SNHL [Honda & Griffith 2022].
• Heterozygotes do not develop SLC26A4-SNHL.

Offspring of a proband. The offspring of an individual with biallelic SLC26A4 pathogenic variants are obligate heterozygotes for an SLC26A4 pathogenic variant.

Other family members. Each sib of the proband's parents has a 50% probability of being heterozygous for an SLC26A4 pathogenic variant.

Heterozygote detection. Heterozygote testing for relatives of an individual with SLC26A4-SNHL requires prior identification of the SLC26A4 pathogenic variants.

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.

Sibs of an individual with SNHL and one identified SLC26A4 pathogenic variant. If only one SLC26A4 pathogenic variant has been identified in a person with SNHL, evaluation of sibs should be individualized and may include computed tomography to assess inner ear anatomy and audiometry. Molecular genetic testing may be of questionable value, and consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse may facilitate decision making. See Molecular Genetics, Other molecular mechanisms under investigation.

Family planning

• The optimal time for clarification of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling to young adults with SLC26A4-SNHL or who may be heterozygous for an SLC26A4 pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once biallelic SLC26A4 pathogenic variants have been identified in the proband, prenatal and preimplantation genetic testing are possible.

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

SLC26A4 encodes the protein pendrin, which functions as a nonspecific exchanger of anions (e.g., chloride and iodide) and bases (e.g., HCO₃⁻ and OH⁻) across the apical plasma membranes of epithelial cells. Pendrin is expressed in a limited number of tissues, including the inner ear, thyroid, kidney, and lungs (where it is expressed in the epithelial cells of the respiratory tract). In the inner ear, absence or reduced function of pendrin leads to acidification of endolymphatic fluid and antenatal formation of enlarged vestibular aqueduct and, by unknown means, degeneration of the sensory cells in the cochlea [Griffith & Wangemann 2011, Wangemann 2011]. The thyroid phenotype in SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL) results from reduced iodide efflux into the thyroid follicle and impaired iodide organification [Honda & Griffith 2022].

Mechanism of disease causation. Loss of function

Other molecular mechanisms under investigation. In individuals with a phenotype consistent with SLC26A4-SNHL and a single identified SLC26A4 pathogenic variant (i.e., individuals with a postulated "missing variant"), noncoding variants affecting the level of expression of SLC26A4 could be involved.

In individuals of Chinese, Korean, and Japanese ancestry with enlarged vestibular aqueduct (EVA), 67%-90% have biallelic SLC26A4 pathogenic variants (called the M2 genotype), and 8%-21% have a single SLC26A4 pathogenic variant (called the M1 genotype) [Choi et al 2009, Miyagawa et al 2014, Honda & Griffith 2022].

In individuals of northern European ancestry with EVA, about 25% have biallelic SLC26A4 pathogenic variants (M2 genotype), ~25% have a single SLC26A4 pathogenic variant (M1 genotype), and the remaining 50% do not have any identifiable SLC26A4 pathogenic variants (called the M0 genotype). These percentages suggest the existence of an undetected/unrecognized SLC26A4 pathogenic variant in a noncoding region in individuals in this ethnic group with EVA and an M1 genotype. Although to date no such SLC26A4 pathogenic variants have been identified, a shared haplotype (referred to as the "Caucasian" EVA [CEVA] haplotype) has been identified in many individuals with the M1 genotype. The CEVA haplotype is a polymorphism comprised of 12 single-nucleotide variants spanning a 0.89-Mb region extending from upstream of PRKAR2B to intron 3 of SLC26A4 [Chattaraj et al 2017, Smits et al 2022] that is present in 3% of the non-Finnish European population.

Although the CEVA haplotype is frequently reported in trans in affected persons with one SLC26A4 pathogenic variant [Chattaraj et al 2017], a detailed study using short- and long-read whole-genome sequencing and optical mapping could not identify any variant in the CEVA haplotype as pathogenic [Smits et al 2022]. As the CEVA haplotype does not always segregate with the SLC26A4-SNHL phenotype and no functional evidence of its effect on gene expression has been identified, the CEVA haplotype is considered a variant of uncertain significance (VUS). Thus, a definitive diagnosis of SLC26A4-SNHL cannot be made even if a SLC26A4 pathogenic variant is confirmed in trans with the CEVA haplotype.

Variants of uncertain significance. The noncoding variant 2343+69C>A, reported by Yuan et al [2012] in one individual, remains a VUS, as information on the phenotype or other variants in trans was not provided.

If molecular genetic testing reveals only one SLC26A4 pathogenic (or likely pathogenic variant) in a symptomatic proband or if there is an SLC26A4 variant of uncertain significance, perchlorate discharge testing may be considered. Although now rarely used, this test measures the amount of radioactive iodine released from the thyroid gland after administering perchlorate, which displaces iodine from the thyroid, thereby revealing a potential defect in iodine uptake and transport due to faulty pendrin function.

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 also actively involved in research in individuals with a phenotype suggestive of SLC26A4-SNHL in whom only one SLC26A4 pathogenic variant has been identified. For questions about hearing loss and the diagnosis of SLC26A4-SNHL, email ude.awoiu@lrom. Lab website: morl.lab.uiowa.edu

Amanda M Odell, MS, LGC, is a licensed and board-certified genetic counselor who specializes in hearing loss and deafness genetics at the University of Iowa. She works with the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offers genetic testing for hearing loss. Amanda is actively involved in translational research studies for hearing loss, including genotype-phenotype studies, genetic counseling for persons with hearing loss, and implementation of genetic evaluation for hearing loss.

Hela Azaiez, MS, PhD, is a human geneticist specializing in the molecular genetics and genomics of hearing loss at the Department of Otolaryngology at the University of Iowa. 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, particularly when no causative variant has been identified through molecular genetic testing of known genes associated with hearing loss.

Acknowledgments

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

Author History

Fatemeh Alasti, PhD; University of Iowa (2011-2017)
Hela Azaiez, MS, PhD (2025-present)
Lorraine A Everett, MD; National Institutes of Health (1998-2001)
Eric D Green, MD, PhD; National Institutes of Health (1998-2001)
Yoichiro Iwasa, MD, PhD; University of Iowa (2020-2025)
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Amanda M Odell, MS, LGC (2020-present)
Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD; University of Antwerp (1998-2017)
Peter Van Hauwe; University of Antwerp (1998-2001)

Revision History

• 9 January 2025 (bp) Comprehensive update posted live
• 19 October 2017 (bp) Comprehensive update posted live
• 29 May 2014 (me) Comprehensive update posted live
• 22 December 2011 (me) Comprehensive update posted live
• 2 April 2009 (me) Comprehensive update posted live
• 31 August 2006 (me) Comprehensive update posted to live Web site
• 28 June 2004 (me) Comprehensive update posted to live Web site
• 1 May 2001 (me) Comprehensive update posted to live Web site
• 28 September 1998 (pb) Review posted to live Web site
• 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe

Literature Cited

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