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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Pendred syndrome and DFNB4 comprise a phenotypic spectrum of hearing loss with or without other findings. Pendred syndrome is characterized by severe-to-profound bilateral sensorineural hearing impairment that is usually congenital and non-progressive, vestibular dysfunction, temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood. Variability of findings is considerable, even within the same family. DFNB4 is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and temporal bone abnormalities. Thyroid defects are not seen in DFNB4.
Diagnosis/testing. Pendred syndrome and DFNB4 are diagnosed clinically in individuals with (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; and (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia (the presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia). In addition, individuals with Pendred syndrome have either an abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout cannot be performed). The only two genes known to be associated with Pendred syndrome/DFNB4 are SLC26A4 (~50% of affected individuals) and FOXI1 (~1% of affected individuals, suggesting further genetic heterogeneity). Sequence analysis identifies disease-causing mutations in approximately 50% of affected individuals from multiplex families and 20% of individuals from simplex families; such testing is clinically available. FOXI1 testing is available on a research basis only.
Management. Treatment of manifestations: hearing habituation, hearing aids, and educational programs designed for the hearing impaired; consideration of cochlear implantation in individuals with severe-to-profound deafness. Standard treatment of abnormal thyroid function. Surveillance: semiannual or annual assessment of hearing and endocrine function. Repeat audiometry initially every three to six months if hearing loss is progressive. Agents/circumstances to avoid: weightlifting and contact sports.
Genetic counseling. Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible when the family-specific mutations are known.
Pendred syndrome and DFNB4 comprise a phenotypic spectrum caused by mutations in SLC26A4 [Campbell et al 2001] and FOXI1 [Yang et al 2007].
Pendred syndrome is diagnosed clinically in individuals with the following:
Sensorineural hearing impairment that is usually congenital, non-progressive, and severe to profound as measured by auditory brain stem response testing (ABR) or pure tone audiometry. For evaluation of hearing loss, see Deafness and Hereditary Hearing Loss Overview.
Bilateral dilation of the vestibular aqueduct (DVA) (also called enlarged vestibular aqueduct [EVA]) with or without cochlear hypoplasia, in which the labyrinth has one and one-half cochlear turns as opposed to the normal two and three-quarters turns. The presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia.
An abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout cannot be performed). Perchlorate discharge tests have a false negative rate of approximately 5%.
DFNB4 is diagnosed clinically in individuals with the following:
Sensorineural hearing impairment that may be congenital, is often progressive and may become severe to profound as measured by auditory brain stem response testing (ABR) or pure tone audiometry
DVA (EVA) with an otherwise normal bony labyrinth
Normal thyroid function
Perchlorate discharge testing. In individuals with Pendred syndrome, serum thyroglobulin levels may be elevated and a perchlorate challenge shows excessive release of iodine from the thyroid gland. The test uses perchlorate to displace intravenously infused radiolabeled iodide, which accumulates in the thyrocyte secondary to abnormal function of pendrin, the protein encoded by SLC26A4. Normally, iodide is transported into the colloid where it is rapidly bound to thyroglobulin; discharge of unincorporated iodide is less than 10% two hours after administration of perchlorate. In individuals with Pendred syndrome, discharge is greater than 15% and may be as high as 80%.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. The two genes known to be associated with Pendred syndrome/DFNB4 are SLC26A4 and FOXI1 [Yang et al 2007].
Clinical testing
Targeted mutation analysis. Three recurrent mutations in SLC26A4 – p.Leu236Pro (26%), p.Thr416Pro (15%), and c.1001+1G>A (also known as IVS8+1G>A) (14%) – account for 50% of the Pendred syndrome/DFNB4 alleles in Caucasians of northern European descent who have a confirmed diagnosis of Pendred syndrome [Coyle et al 1998, Campbell et al 2001]. The recurrent mutation p.His723Arg accounts for 53% of alleles among Japanese [Tsukamoto et al 2003].
Mutation scanning. The sensitivity of mutation scanning for disease-causing mutations is technique dependent. Denaturing high-performance liquid chromatography (DHPLC) has been shown to detect 100% of allelic variants in an SLC26A4 panel of 41 different mutations. Single-strand conformational polymorphism analysis (SSCP) detected only 63% of the same allelic variants, with detection of two of the most common mutations (p.Leu236Pro, c.1001+1G>A [IVS8+1G>A]) being inconsistent [Prasad et al 2004].
Sequence analysis. Sequencing of all 21 exons (20 coding exons) and splice sites identifies 100% of disease-causing mutations in SLC26A4. In one-third of families segregating a disease-causing mutation in SLC26A4, only one mutation is found (one-,sixth of all individuals with a Pendred syndrome phenotype) [Campbell et al 2001, Park et al 2003].
Deletion/duplication analysis. Deletions of single exons and multiexons have been reported [Pera et al 2008b].
Research testing. Yang and colleagues recently showed that mutations in the forkhead transcription factor FOXI1 contribute to the Pendred syndrome/DFNB4 phenotype [Yang et al 2007].
In two families, persons with DVA demonstrated double heterozygosity in that they had single mutations in both SLC26A4 and FOXI1. To support of the disease-causing nature of this genotype, the investigators showed that FOXI1 activates transcription of SLC26A4 by binding to a 5’-conserved cis-acting promoter element. In addition to the FOXI1 mutations they identified compromised transactivation ability.
In other families with Pendred syndrome/DFNB4, Yang and colleagues found mutations in the promoter site of SLC26A4 that abolishes FOXI1-mediated activation of gene transcription.
Table 1 summarizes molecular genetic testing for Pendred syndrome/DFNB4.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| SLC26A4 | Targeted mutation analysis | p.Leu236Pro, p.Thr416Pro, c.1001+1G>A1 | 25% | Clinical
 |
| Mutation scanning | Sequence variants | ~50% 2 | ||
| Sequence analysis | ~50% 3 | |||
| Deletion/ duplication analysis 4 | Exonic, multiexonic, or whole-gene deletions | Unknown | ||
| FOXI1 | Sequence analysis | Sequence variants | 1% | Research only |
1. These specific mutations are common only in persons of northern European descent; mutations included in a detection panel may vary among laboratories.
2. Results of mutation scanning by DHPLC; other scanning techniques may be less sensitive.
3. SLC26A4 mutations are identified in 50% of multiplex families segregating a Pendred syndrome phenotype.
4. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array CGH may be used.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming/establishing the diagnosis in a proband
In a child with severe-to-profound congenital deafness in whom the clinical history and physical examination are consistent with the diagnosis of autosomal recessive nonsyndromic hearing loss, the first test that should be ordered is molecular genetic testing of GJB2 (see Nonsyndromic Hearing Loss and Deafness, DFNB1).
If GJB2 molecular genetic testing does not identify two disease-causing mutations, computed tomography (CT) or magnetic resonance imaging (MRI) of the temporal bones should be considered to evaluate for DVA and Mondini dysplasia. The presence of either of these temporal bone anomalies warrants molecular genetic testing of SLC26A4. In most children with Pendred syndrome, thyroid enlargement will not be present. Perchlorate testing is not widely available and with molecular genetic testing, not essential to diagnose Pendred syndrome.
High-resolution CT or MRI of the temporal bones should be completed in all children with progressive sensorineural hearing loss to evaluate for DVA. If an enlarged vestibular aqueduct is observed, molecular genetic testing of SLC26A4 is warranted.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
The only phenotypes known to be associated with mutations in SLC26A4 are Pendred syndrome and DFNB4.
Pendred syndrome is characterized by sensorineural hearing impairment, temporal bone anomalies, and the development of euthyroid goiter in late childhood to early adulthood. Variability in hearing loss and thyroid disease is considerable, even within the same family [Napiontek et al 2004].
Hearing impairment. The degree of hearing impairment and its presentation can vary. Classically, the hearing loss is bilateral, severe to profound, and congenital (or prelingual). However, in some instances, hearing loss may be later in onset and progressive. In a number of individuals reported, progressive postlingual hearing impairment has developed following head injury [Luxon et al 2003]. The association with head injury suggests that these individuals may have had an inner-ear malformation such as a dilation of the vestibular aqueduct (DVA). In some individuals, vertigo can precede or accompany fluctuations in hearing [Sugiura et al 2005].
Vestibular dysfunction. Objective evidence of vestibular dysfunction can be demonstrated in 66% of individuals with Pendred syndrome and ranges from mild unilateral canal paresis to gross bilateral absence of function. Vestibular dysfunction should be suspected in infants with normal motor development who episodically experience difficulty walking.
Temporal bone abnormalities. The temporal bones are abnormal radiologically in most, if not all, persons with Pendred syndrome [Goldfeld et al 2005]; however, universal agreement as to the type of abnormality is lacking. This ambiguity reflects imprecision in defining the bony anatomic defect. In a study of individuals homozygous for the same mutation in SLC26A4, high-resolution CT was used to assess temporal bone anatomy. Absence of the upper turn of the cochlea (diagnosed when the interscalar septum cannot be seen between the upper and middle turns) and deficiency of the modiolus (diagnosed when a bony polyhedral structure centered on the cochlea is not apparent on a midmodiolar section) were reported by Goldfeld et al [2005] in 75% and 100% of ears, respectively. DVA, defined by width in the middle portion of the descending limb of the vestibular aqueduct of greater than 1.5 mm, was observed 80% of the time [Goldfeld et al 2005].
These findings suggest that deficiency of the modiolus is the most common anomaly in Pendred syndrome. Affected siblings may be discordant for temporal bone anomalies [Goldfeld et al 2005].
Goiter. Approximately 75% of individuals with Pendred syndrome have evidence of goiter on clinical examination. Goiter develops in late childhood or early puberty in approximately 40% of individuals; in the remainder, it develops in early adult life. Marked intrafamilial variability exists [Van Hauwe et al 1998]. While many individuals with Pendred syndrome are started on thyroxine, only approximately 10% have abnormal thyroid function as defined by a serum TSH level greater than 5 mU/L. Abnormal thyroid function studies in the absence of a goiter have not been reported.
DFNB4 is characterized by sensorineural hearing impairment in the absence of overt abnormalities (i.e., nonsyndromic hearing loss), although CT or MRI of the temporal bones reveals DVA. Thyroid defects are not seen.
Hearing impairment. The degree of hearing impairment and its presentation can vary. Many persons with DVA are born with normal hearing and progressively become hearing impaired during childhood. Although several reports describe a correlation between the size of the DVA and the degree of hearing loss, a strict correlation has not been established [Berrettini et al 2005].
Vestibular dysfunction. Persons with DVA may deny vestibular disturbances although vestibular deficits can be demonstrated by caloric testing. When DVA is unilateral, there is no strict correlation between the side of the vestibular deficit and the side of the vestibular enlargement [Berrettini et al 2005].
Temporal bone abnormalities. DVA is the most common imaging finding in persons with sensorineural hearing loss dating from infancy or childhood. In a study of families with a DFNB4 phenotype, Tsukamoto and colleagues reported SLC26A4 mutations in 75% of probands [Tsukamoto et al 2003]. However, in simplex cases (i.e., a single occurrence in a family) the prevalence of SLC26A4 mutations is much lower [Berrettini et al 2005]. DVA can be bilateral or unilateral.
Functional studies have suggested that missense SLC26A4 mutations that retain residual iodide transport function are more likely to be associated with DFNB4 than with Pendred syndrome [Scott et al 2000]. However, predicting the likely functional significance of a missense mutation is difficult. The two parameters traditionally used - low incidence in a control population and substitution of an evolutionarily conserved amino acid - are not reliable. Pera and colleagues have shown that the addition or omission of proline, or the addition or omission of charged amino acids in the sequence of SLC26A4 is be a better predictor of altered SLC26A4 function in the absence of direct functional tests [Pera et al 2008a].
Frequency of episodes of vertigo and the rate of progression of hearing loss may be mutation dependent [Sugiura et al 2005].
That Pendred syndrome and DFNB4 should be considered together is supported by numerous studies reporting variable expressivity of Pendred syndrome and, in particular, its thyroid manifestations [Reardon et al 1997].
Although the prevalence of Pendred syndrome is unknown, Fraser [1965] calculated that it accounts for 7.5% of all congenital deafness. If these data are representative, Pendred syndrome is a common cause of congenital hearing impairment. When Pendred syndrome and DFNB4 are considered part of the same disease spectrum, prevalence figures are very high. A study of 274 East Asians and 318 South Asians with deafness demonstrated mutations in SLC26A4 in approximately 5.5% of both groups [Park et al 2003]. However, in order to establish the importance of mutations in SLC26A4 as a cause of hearing impairment in individuals with nonsyndromic deafness, screening of a broader deaf population will be necessary.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Congenital inherited hearing impairment. Congenital (or prelingual) inherited hearing impairment affects approximately one of 2,000 newborns. Thirty percent of these babies have additional anomalies, making the diagnosis of a syndromic form of hearing impairment possible (see Deafness and Hereditary Hearing Loss Overview). Although dilation of the vestibular aqueduct (DVA) with or without cochlear hypoplasia is seen in 85% of individuals with Pendred syndrome, neither DVA nor cochlear hypoplasia is specific for Pendred syndrome; individually, therefore, they are of limited diagnostic value. Approximately 20% of children who represent simplex cases (i.e., the only affected individual in the family) have DVA and disease-causing mutations in SLC26A4 [Campbell et al 2001].
Abnormal perchlorate test. The perchlorate test is abnormal in a number of thyroid conditions, including Hashimoto's thyroiditis, total iodide organification deficiency, and I131-treated thyrotoxicosis.
Congenital hypothyroidism with sensorineural hearing loss. Sporadic and endemic congenital hypothyroidism associated with sensorineural hearing impairment are clinically similar to Pendred syndrome but genetically distinct.
Resistance to thyroid hormone. Although the syndrome of resistance to thyroid hormone (RTH) is typically inherited in an autosomal dominant manner, one exceptional consanguineous kindred in which RTH was inherited in an autosomal recessive manner has been described. Two of six children had severe sensorineural hearing impairment and goiter and a large deletion (detected by karyotyping) on chromosome 3 that included the thyroid receptor β (TRMβ) gene.
Autoimmune thyroid diseases. Autoimmune thyroid diseases (AITD), including Graves' disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, are caused by multiple genetic and environmental factors. Candidate genes involved in this group of diseases include genes that regulate immune response and/or thyroid physiology. An association study comparing alleles of D7S496 and D7S2459 with AITD phenotype suggests that SLC26A4 should be added to the list of susceptibility genes for GD [Hadj Kacem et al 2003].
To establish the extent of involvement in an individual diagnosed with Pendred syndrome/DFNB4, the following evaluations are recommended:
Assessment of auditory acuity (ABR emission testing, pure tone audiometry)
Thin-cut CT of the temporal bones to identify structural abnormalities
Vestibular function studies
Perchlorate discharge test and thyroid function tests (T3, T4, and TSH)
The following are appropriate:
Hearing habilitation (hearing aids as early as possible)
Consideration of cochlear implantation in individuals with severe to profound deafness
Educational programs designed for individuals with hearing impairment
Treatment of abnormal thyroid function, if present, in the standard manner
Surveillance includes:
Semiannual or annual examination by a physician who is familiar with hereditary hearing impairment
Semiannual or annual examination by an endocrinologist familiar with Pendred syndrome
Repeat audiometry initially every three to six months if hearing loss is progressive
Based on anecdotal reports that increased intracranial pressure in individuals with dilation of the vestibular aqueduct (DVA) can trigger a decline in hearing, some physicians recommend avoiding activities like weightlifting and contact sports.
At-risk relatives should be evaluated for hearing loss, vestibular structure, and thyroid abnormality in the same manner as an affected individual at initial diagnosis.
If the disease-causing mutations in the family are known, molecular genetic testing of sibs is indicated shortly after birth so that appropriate and early support and management can be provided to the child and family.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner.
Parents of a proband
Parents are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation.
Heterozygotes are asymptomatic.
Sibs of a proband
At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes are asymptomatic.
Offspring of a proband. The offspring of an individual with Pendred syndrome/DFNB4 are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.
Carrier testing for reproductive partners of individuals who are identified as being mutation carriers is clinically available.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
The following points are noteworthy:
Communication with individuals who are deaf requires the services of a skilled interpreter.
Deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." In fact, having a child with deafness may be preferred over having a child with normal hearing.
Many deaf people are interested in obtaining information about the cause of their own deafness — including information on medical, educational, and social services — rather than information about prevention, reproduction, or family planning. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears and to ascertain and address the questions and concerns of the family/individual.
The use of certain terms is preferred: "probability" or "chance" vs "risk"; "deaf" and "hard-of-hearing" vs "hearing-impaired." Terms such as "affected," "abnormal," and "disease-causing" should be avoided.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from cells obtained from amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal diagnosis of hearing status are uncommon and require genetic counseling.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|---|
| DFNB4 | SLC26A4 | 7q31 | Pendrin |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 274600 | PENDRED SYNDROME; PDS |
| 600791 | DEAFNESS, NEUROSENSORY, AUTOSOMAL RECESSIVE 4; DFNB4 |
| 605646 | SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4 |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| SLC26A4 | SLC26A4 | 5172 (MIM No. 605646) | SLC26A4 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
The relationship between pendrin, the protein encoded by SLC26A4, and deafness has been investigated extensively in mouse mutants segregating a targeted deletion of Slc26a4. Endolymph volume in homozygous null mice (Slc26a4-/-) is increased and tissue mass in areas occupied by type I and II fibrocytes is reduced. Slc26a4-/- mice lack an endocochlear potential, which is generated across the basal cell barrier of the stria vascularis by the potassium channel KCNJ10 and localizes to the intermediate cells. Normal endolymphatic K+ concentrations suggest that absent or dysfunctional pendrin results in a secondary loss of KCNJ10 protein expression and the endocochlear potential. Loss of the endocochlear potential may be the direct cause of deafness in Pendred syndrome/DFNB4 [Wangemann et al 2004].
Recent data from Yang et al [2007] are consistent with a dosage-dependent model for the molecular pathogenesis of Pendred syndrome/DFNB4 that involves not only SLC26A4 but also FOXI1, which regulates its transcriptional regulatory machinery.
Normal allelic variants. SLC26A4 belongs to the solute carrier 26 gene family and has significant homology to 13 other proteins that function as sulfate transporters. These sequences cross a large taxonomic span including animals, plants, and yeast, although the two closest relatives of pendrin are the human DRA (down-regulated in adenoma) and DTD (diastrophic dysplasia) genes. The DRA and SLC26A4 genes are positioned tail to tail and separated by only 48 kb, suggesting an evolutionary relationship.
Pathologic allelic variants. See Table 2. More than 170 different mutations in SLC26A4 have been reported as causing Pendred syndrome/DFNB4 [Prasad et al 2004, Molecular Otolaryngology Research Laboratory]. Of these mutations, the majority are seen only in single families [Campbell et al 2001].
Three mutations (p.Leu236Pro, p.Thr416Pro, and c.1001+1G>A) are seen more frequently than other mutations in the Caucasian population of northern European descent and account for 50% of the Pendred disease alleles in individuals with a confirmed diagnosis of Pendred syndrome in this ethnic group [Coyle et al 1998, Campbell et al 2001]. Each of these recurrent mutations occurs on distinct but common haplotypes, supporting the notion for common founders in these independently ascertained families [Coyle et al 1998, Van Hauwe et al 1998, Park et al 2003]. However, all ethnic groups have a unique diverse mutant allele series with a few prevalent founder mutations.
| DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.707T>C | p.Leu236Pro | NM_000441.1NP_000432.1 |
| c.1001+1G>A (IVS8+1G>A) | -- | |
| c.1246A>C | p.Thr416Pro |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society.
1. Variant designation that does not conform to current naming conventions
Normal gene product. The SLC26A4 gene encodes the 780-amino acid (86-kd) protein, pendrin, which functions as a chloride and iodide transporter. The mRNA product is approximately 5 kb long, with an open reading frame of 2343 base pairs distributed across 21 exons. The predicted amino acid sequence initially suggested a highly hydrophobic protein with 11 transmembrane domains; however, Royaux et al [2000] have shown that the carboxy terminus is intracellular, implying that an additional alpha helix spans the cell membrane [Royaux et al 2000]. In an analysis of data from ten transmembrane prediction programs, eight to 13 transmembrane domains are predicted; 12 transmembrane domains are predicted by four of the programs, including MEMSAT2, ranked by a recent review as one of the most accurate prediction programs [Simon et al 2001].
Abnormal gene product. A splice site mutation that causes a G-to-A transition at a position in the 5' splice consensus sequence that is 100% conserved has been identified in several families with Pendred syndrome [Coyle et al 1998, Van Hauwe et al 1998]. This type of mutation almost always leads to aberrant splicing, either by exon skipping or by the use of a cryptic splice site. The exact effect on mRNA has not been determined because amplication of RT-PCR from cDNA of lymphoblastoid cell lines has been unsuccessful, even by nested PCR [Van Hauwe & Van Camp, unpublished results].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Pendred syndrome
NCBI Genes and Disease
Pendred syndrome
American Society for Deaf Children
3820 Hartzdale Drive
Camp Hill PA 17011
Phone: 800-942-2732 (parent hotline); 866-895-4206 (toll free); 717-703-0073 (voice/TTY)
Fax: 717-909-5599
Email: asdc@deafchildren.org
www.deafchildren.org
National Association of the Deaf
8630 Fenton Street Suite 820
Silver Spring MD 20910
Phone: 301-587-1788 (voice); 301-587-1789 (TTY)
Fax: 301-587-1791
Email: NADinfo@nad.org
www.nad.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Lorraine A Everett, MD; National Institutes of Health (1998-2001)
Eric D Green, MD, PhD; National Institutes of Health (1998-2001)
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD (1998-present)
Peter Van Hauwe; University of Antwerp (1998-2001)
2 April 2009 (me) Comprehensive update posted live
2 July 2008 (cd) Revision: deletion/duplication analysis available clinically
31 August 2006 (me) Comprehensive update posted to live Web site
15 July 2004 (rjhs) Revision: use of an interpreter
28 June 2004 (me) Comprehensive update posted to live Web site
2 July 2003 (rjhs) Revisions
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
