{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:32:10Z","timestamp":1782448330147,"version":"3.54.5"},"reference-count":121,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.<\/jats:p>","DOI":"10.3390\/genes12111669","type":"journal-article","created":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T22:06:16Z","timestamp":1635113176000},"page":"1669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-4807","authenticated-orcid":false,"given":"Cedrik","family":"Tekendo-Ngongang","sequence":"first","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Grochowsky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"Solomon","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho T.","family":"Yano","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1542\/peds.2010-3500","article-title":"Health supervision for children with fragile X syndrome","volume":"127","author":"Hersh","year":"2011","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1542\/peds.2013-4301","article-title":"Fragile X syndrome: A review of associated medical problems","volume":"134","author":"Kidd","year":"2014","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1542\/peds.89.3.395","article-title":"Girls with fragile X syndrome: Physical and neurocognitive status and outcome","volume":"89","author":"Hagerman","year":"1992","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/s41436-021-01115-y","article-title":"Laboratory testing for fragile X, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Spector","year":"2021","journal-title":"Genet. 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