The WFS1 gene was first associated with autosomal dominant nonsyndromic hearing loss in 2001 (Young et al., PMID: 11709538). Of note, the WFS1 gene has been implicated in autosomal recessive Wolfram syndrome and autosomal dominant Wolfram-like syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, they have been curated separately by this expert panel. The nonsyndromic hearing loss in individuals with heterozygous WFS1 variants is progressive and low frequency which is different from the high frequency hearing loss seen in Wolfram syndrome patients. Generally non-inactivating variants that are mainly located in and around the C-terminal protein domain have been found in families with isolated hearing loss; thus, loss of function variants were not scored in this curation. At least 35 unique variants (missense and in-frame deletions/duplications) that have been reported in 43 probands in 15 publications are included in this curation (PMIDs: 11709538, 11709537, 12073007, 12181639, 17492394, 18688868, 24909696, 25250959, 28802351, 29529044, 33297549, 34222109, 34599366, 37041640, 36958120). More cases that are reported in the literature are not included in this curation, as definitive status was reached (PMID: 34599366). Variants in this gene segregated with disease in at least 60 family members in several families (PMIDs: 11709537, 12073007, 12181639, 25250959, 28802351). This gene-disease relationship is supported by expression data and a knockin mouse model with a variant present in human patients which recapitulated the deafness phenotype (PMIDs: 12649740, 27341211, 37386014). One study showed reduction in myelin in Wolfram patients compared to both healthy and diabetic controls (PMID: 26888576). This study was not scored since it is not specific to isolated hearing loss but disrupted myelination of auditory nerves is a plausible explanation for hearing loss. In summary, WFS1 is definitively associated with autosomal dominant nonsyndromic hearing loss. 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 GCEP on the meeting date June 25th, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.