Submission Details

The association between SLC26A4 and autosomal recessive Pendred syndrome is well-established and over 500 variants have been reported, including missense, nonsense, frameshift, splice, in-frame indel, and large deletion variants. The hearing loss associated with SLC26A4 is typically congenital, pre-, or peri-lingual in onset and caused by enlarged vestibular aqueduct (EVA). An incomplete partitioning defect of the cochlea may also be present. Goiter and/or hypothyroidism are an incompletely penetrant feature of Pendred syndrome and may not present until the second decade of life (Pryor 2005, Soh 2015). There may be variable expression of the thyroid features, even within families with the same pathogenic variants. Additionally, a large percentage of individuals with hearing loss and EVA lack variants on one or both alleles of SLC26A4. Individuals with a single mutation appear to be less likely to develop the thyroid features, but may have similar recurrence risks as individuals found to harbor two biallelic pathogenic variants (Pryor 2005, Chattaraj 2014). This gene-disease association is supported by animal models, evidence of expression in the ear and thyroid, and in vitro biochemical studies. In summary, SLC26A4 is definitively associated with autosomal recessive Pendred syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 6/7/2017.