The TIMM8A gene has been associated with X-linked deafness dystonia syndrome (aka Mohr-Tranebjærg syndrome) using the ClinGen Clinical Validity Framework as of 8/18/2017. This association was made using case-level data and experimental data. At least 6 probands in 5 publications with at least 8 unique variants (missense, nonsense, frameshift) have been reported in humans, and variants in this gene segregated with disease in 17 additional family members (PMIDs 11803487, 22736418, 18952432, 17999202). TIMM8A was first associated with this disease in humans in 2000 (Tranebjaerg et al.). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is X-linked LOF. This gene-disease association is supported by functional alteration studies in isolated patient cells as well as non patient cells and expression studies (PMIDs: 11956200, 15254020). In summary, TIMM8A is definitively associated with X-linked deafness dystonia 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 12/19/2017.
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).
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