The relationship between LOXHD1 and autosomal recessive nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/15/2017. Variants in LOXHD1 were first reported in humans with this disease as early as 2009 (Grillet et al., PMID 19732867). At least 16 unique variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 11 probands in 6 publications (PMIDs 26969326, 21465660, 19732867). Variants in this gene segregated with disease in 13 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is thought to be that loss of function of the LOXHD1 protein is deleterious to hair cell function (PMID: 19732867). This gene-disease association is supported by animal an animal model that also demonstrated expression of LOXHD1 in the ear (PMID: 19732867). Studies have also identified this gene to be related to dominant late-onset Fuchs corneal dystrophy (PMID: 27121161, 22341973, 23585771). In summary, LOXHD1 is definitively associated with ARNSHL. 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 5/8/2018
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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