FMR1 was first reported in relation to X-linked fragile X syndrome in 1991 (Kremer et al., 1675488). The majority of cases are a result of an unstable expanded trinucleotide (CGG)n repeat sequence of greater than 200 repeats in the 5-prime untranslated region of FMR1; however, at least 10 unique variants (repeat expansion, missense, splice, nonsense, frameshift, insertion and large deletions) have been reported in humans. Other phenotypic presentations (Fragile X Tremor Ataxia Syndrome, Primary Ovarian Insufficiency) may be observed in individuals with FMR1 premutations (defined as 55-200 repeats). For the purposes of this curation, however, we have chosen to only evaluate evidence related to classic Fragile X syndrome. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 10 probands in 8 publications (1675488, 8490650, 8069307, 7670500, 21267007, 24448548, 25693964, 28176767). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is hemizygous loss of function. This gene-disease association is supported by animal models, expression studies and functional assays. In summary, FMR1 is definitively associated with X-linked fragile X 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 Intellectual Disability and Autism Working Group on 6/3/2019 (SOP Version 6).
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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