{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:57:09Z","timestamp":1790686629704,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israeli Science Foundation","doi-asserted-by":"publisher","award":["1342\/23"],"award-info":[{"award-number":["1342\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1342\/23"],"award-info":[{"award-number":["1342\/23"]}],"id":[{"id":"https:\/\/ror.org\/04sazxf24","id-type":"ROR","asserted-by":"publisher"}]},{"name":"MAVRI","award":["3531\/26"],"award-info":[{"award-number":["3531\/26"]}]},{"name":"G. Baum"},{"name":"Pulmonary Clinic, Israel Lung Association","award":["36116"],"award-info":[{"award-number":["36116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Excessive telomere shortening contributes to pulmonary fibrosis (PF), with at least 30% of familial cases attributed to telomere biology disorders (TBDs). However, TBD-associated PF remains underdiagnosed because of unidentified disease-causing mutations and limited referral for telomere and genetic testing. Here, we combined telomeric restriction fragment analysis, telomere analysis by a long-read Nanopore sequencing method (NanoTelSeq), exome sequencing (ES), and optical genome mapping (OGM) to investigate the underlying cause of disease in a family affected by PF, microcephaly, and premature hair graying. We identified a familial balanced translocation associated with short telomeres, which involved a chromosome 3 breakpoint within the non-coding telomerase RNA component (TERC) gene, disrupting the 451-nucleotide telomerase RNA. Establishing the diagnosis enabled a TBD-tailored protocol and successful lung transplantation in the proband at age 49. These findings identified structural disruption of TERC as a previously unrecognized cause of TBD and broadened the genetic landscape of TBD beyond splicing, single nucleotide substitutions, and insertion\/deletion variants. Furthermore, they demonatrate the importance of routine telomere length measurement alongside comprehensive genomic testing in familial PF.<\/jats:p>","DOI":"10.3390\/ijms27198667","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Balanced Chromosomal Rearrangement Disrupting the Telomerase RNA Component Gene Causes Short Telomere-Mediated Pulmonary Fibrosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2564-8660","authenticated-orcid":false,"given":"Noa","family":"Hourvitz","sequence":"first","affiliation":[{"name":"Department of Genetics, The Silberman Institute for Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"},{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Neustadter-Blackman","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Silberman Institute for Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-3326","authenticated-orcid":false,"given":"Avraham","family":"Unterman","sequence":"additional","affiliation":[{"name":"Pulmonary Fibrosis Center of Excellence, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906,  Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-9798","authenticated-orcid":false,"given":"Riham","family":"Smoom","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Silberman Institute for Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Mory","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hila","family":"Lederman Nahemias","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3621","authenticated-orcid":false,"given":"Alina","family":"Kurolap","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-464X","authenticated-orcid":false,"given":"Uri","family":"Hamiel","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mordechai R.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel"},{"name":"Pulmonary Institute, Rabin Medical Center, Petah-Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagit","family":"Baris Feldman","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-435X","authenticated-orcid":false,"given":"Yehuda","family":"Tzfati","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Silberman Institute for Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem 91904, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-9646","authenticated-orcid":false,"given":"Daphna","family":"Marom","sequence":"additional","affiliation":[{"name":"The Genetic Institute and Genomics Center, Tel Aviv Sourasky University Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41576-022-00527-z","article-title":"Genetics of human telomere biology disorders","volume":"24","author":"Revy","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.healun.2021.11.008","article-title":"Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease","volume":"41","author":"Alder","year":"2022","journal-title":"J. Heart Lung Transplant."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1152\/physrev.00046.2021","article-title":"Telomere-mediated lung disease","volume":"102","author":"Alder","year":"2022","journal-title":"Physiol. 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