ADAMTS18 was first reported in relation to autosomal recessive Microcornea-Myopic Chorioretinal Atrophy in 2013 (Aldahmesh, 23818446). This syndrome is characterized by novel ocular findings in addition to distinct facial features including telecanthus in some patients, wide nose or broad nasal tip and posterior rotation of the ears. Additional studies however were limited to phenotypes primarily involving visual function (23356391, 24874986). At least 8 variants (5 missense, 3 nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Case level data includes predicted null variants that have been reported in 4 probands in 2 publications (23818446, 24874986) and missense variants predicted to impact gene function reported in 5 probands (23818446, 24874986, 23356391). In the 8 families with variants in this gene, 7 variants segregated with disease in 6 additional affected family members. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by animal models, expression studies, in vivo functional assays in model organisms contributing to the experimental evidence scoring (2 pts.) (21862674, 23356391). Peluso et al. showed expression of ADAMTS18 from cDNA isolated from retina using RT-PCR with gene specific primers and confirmed by Sanger sequencing. As well as investigating expression in adult mice at P60 using In situ hybridization and found Adamts18 expressed in retinal ganglion cell layer, inner nuclear layer, and RPE. In vivo assays to determine the function of ADAMTS18 were performed in medaka fish using a light-induced photoreceptor degeneration assay and found that fish with translation-blocking morpholinos had reduced thicknes in the outer segments along with fewer Rhodopsin positive cells indicating photoreceptor cells loss indicative of retinal degeneration (Peluso, 23356391). These studies point to the role of ADAMTS18 in visual development and function. ● DEFINITIVE: In summary, there is strong evidence to support the relationship between ADAMTS18 and autosomal recessive Microcornea-Myopic Chorioretinal Atrophy
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