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However, non\u2010coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA\u2010seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA\u2010seq, we delineated a deep intronic\n                    <jats:italic>TAPT1<\/jats:italic>\n                    mutation (c.1237\u201052 G&gt;A) that segregated with the disease. Using SI\u2010NET\u2010seq, we document that\n                    <jats:italic>TAPT1<\/jats:italic>\n                    's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre\u2010mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances\n                    <jats:italic>TAPT1<\/jats:italic>\n                    exon 12 skipping, creating a protein\u2010null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease\u2010relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non\u2010coding variants, as well as in illuminating the molecular mechanisms of human diseases.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202216478","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T12:16:17Z","timestamp":1674044177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA\/SI\u2010NET sequencing"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1629-6956","authenticated-orcid":false,"given":"Nasrinsadat","family":"Nabavizadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3170-4823","authenticated-orcid":false,"given":"Annkatrin","family":"Bressin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3286-1422","authenticated-orcid":false,"given":"Mohammad","family":"Shboul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2607-107X","authenticated-orcid":false,"given":"Ricardo","family":"Moreno Traspas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poh Hui","family":"Chia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Bonnard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Szenker\u2010Ravi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-0418","authenticated-orcid":false,"given":"Burak","family":"Sar\u0131ba\u015f","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2546-7614","authenticated-orcid":false,"given":"Emmanuel","family":"Beillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umut","family":"Altunoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4831-0123","authenticated-orcid":false,"given":"Zohreh","family":"Hojati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Drutman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Freier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"El\u2010Khateeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajaa","family":"Fathallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Laurent","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam","family":"Soror","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Arafat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-1608","authenticated-orcid":false,"given":"Nathalie","family":"Escande\u2010Beillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4532-9382","authenticated-orcid":false,"given":"Andreas","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4070-7997","authenticated-orcid":false,"given":"Bruno","family":"Reversade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"BFEMMM202216478_CR1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W (2015) HTSeq\u2010\u2010a python framework to work\u00a0with high\u2010throughput sequencing data. 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