{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:34:36Z","timestamp":1790883276577,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011541","name":"Division of Cancer Epidemiology and Genetics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic <jats:italic>RTEL1<\/jats:italic> variants result in childhood onset dyskeratosis congenita and Hoyeraal\u2010Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD\u2010associated <jats:italic>RTEL1<\/jats:italic> variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono\u2010 or biallelic <jats:italic>RTEL1<\/jats:italic> variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG\u2010AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic <jats:italic>RTEL1<\/jats:italic> variants had an earlier age at diagnosis (median age 35.5 vs. 5.1\u2009years, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and worse overall survival (median age 66.5 vs. 22.9\u2009years, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). There were 257 unique <jats:italic>RTEL1<\/jats:italic> variants reported in 47 publications, and 209 had a gnomAD minor allele frequency &lt;1%. Only 38.3% (80\/209) met pathogenic\/likely pathogenic criteria. Notably, 8 of 209 reported disease\u2010associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with <jats:italic>RTEL1<\/jats:italic> germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.<\/jats:p>","DOI":"10.1002\/ajmg.a.63882","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T07:35:22Z","timestamp":1726472122000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Germline <scp><i>RTEL1<\/i><\/scp> Variants in Telomere Biology Disorders"],"prefix":"10.1002","volume":"197","author":[{"given":"Ashley S.","family":"Thompson","sequence":"first","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute  Bethesda USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marena 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