Pendred Syndrome and Hearing Loss with EVA Test Details
SLC26A4-related hearing loss is unique among inherited hearing impairments in that all individuals with two variants in this gene have a particular abnormality of the inner ear that can be observed by MRI or CT scan of the temporal bone. This abnormality, known as enlarged vestibular aqueducts (EVA) may be seen alone or in combination with Mondini dysplasia (a common cavity malformation of the inner ear). Although variants in this gene are not the only cause of hearing loss with EVA, SLC26A4 contributes significantly to this etiology. As a result, it is recommended that the SLC26A4 gene test be ordered for all individuals with nonsyndromic hearing loss and EVA. This is true even if there is no family history of hearing loss, which is a common presentation in autosomal recessive conditions.
Some individuals with pathogenic SLC26A4 variants also develop goiter (enlargement of the thyroid), though most usually retain normal thyroid function. It has been suggested that the likelihood of having or developing thyroid disease may be correlated with the number of variants (1 vs. 2) identified in the gene (Pryor et al, 2005). Goiter (thyroid enlargement) is seen in ~20% of cases and hypothyroidism can occasionally occur. The combined occurrence of hearing loss, temporal bone abnormalities, and thyroid dysfunction define the SLC26A4-related disorder, Pendred syndrome, which represents the most common syndromic form of deafness.
The incidence of SLC26A4 related hearing loss is approximately 1 in 7500 and variants in this gene may cause up to 5-10% of congenital hearing loss. The hearing loss is typically bilateral severe or profound sensorineural hearing loss, which can be progressive or fluctuating. Variability in the severity of hearing loss is seen, with some individuals exhibiting a milder hearing loss. Autosomal recessive inheritance has been observed, however a large number of individuals with hearing loss and EVA have been found to carry single pathogenic variants in SLC26A4, indicating a more complex genetic etiology.
|SLC26A4||Solute Carrier Family 26, Member 4||605646||7q31|
Testing for the SLC26A4 gene is recommended for individuals with sensorineural hearing loss with temporal bone abnormalities (observed on a CT scan or MRI of the inner ear) including enlarged (dilated) vestibular aqueduct and/or Mondini malformation. This test is also recommended for individuals with hearing loss and goiter or a positive perchlorate discharge test. The presence of one or two pathogenic variants is considered a positive result. Two variants may indicate a higher likelihood of developing thyroid disease.
This test is performed by Sanger sequencing of the coding regions and splice sites of the SLC26A4 gene. This test does not detect large deletions or variants in non-coding regions that could affect gene expression.
Analytical and Clinical Sensitivity
This test is greater than 99.9% accurate in detecting variants in the sequence analyzed. Approximately 50% of individuals with DFNB4 or Pendred syndrome have pathogenic variants in SLC26A4 (Alasti 2014 PMID:20301640).