{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:55:00Z","timestamp":1790394900542,"version":"4.1.0"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","funder":[{"name":"Assistance Publique - H\u00c3\u00b4pitaux de Paris"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2025,2]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n \n MUC1<\/jats:italic>\n is associated with autosomal dominant tubulointerstitial kidney disease, a genetic disorder progressing to kidney failure.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Variations in this gene are not easily diagnosed by conventional methods due to the\n MUC1<\/jats:italic>\n architecture, which contains a variable number of tandem repeats.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Using dedicated bioinformatics tools, we systematically detected the presence of 27dupC most common\n MUC1<\/jats:italic>\n pathogenic variant from exome sequencing data.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n The\n MUC1<\/jats:italic>\n gene is associated with autosomal dominant tubulointerstitial kidney disease (ADTKD), leading to CKD. Current methods of sequencing, such as exome sequencing, rarely detect\n MUC1<\/jats:italic>\n pathogenic variants because of the variable number of tandem repeats (VNTR) in\n MUC1<\/jats:italic>\n exon2. We demonstrated that combining fast read filtering with a sensitive VNTR genotyping strategy enables systematic screening of 27dupC pathogenic\n MUC1<\/jats:italic>\n variant from exome data.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We initially validated our bioinformatics pipeline in a proof-of-concept cohort incorporating exome data from 33 participants with a known\n MUC1<\/jats:italic>\n pathogenic variant identified by Snapshot PCR and confirmed by 54\n MUC1<\/jats:italic>\n -negative individuals for negative control. We then retrospectively analyzed exome sequencing data from January 2019 to October 2023 from 3512 adult participants with nephropathy of unknown origin. Finally, we prospectively validated our pipeline in 825 additional participants enrolled from November 2023.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n SharkVNTyper accurately identified\n MUC1<\/jats:italic>\n variants in 32 of 33 participants and excluded its presence in all the 54 negative controls in the proof-of-concept cohort (sensitivity of 97%, specificity of 100%). Integration of the Shark tool with VNTyper significantly reduced running time from 6\u201312 hours to 5\u201310 minutes per sample, allowing both retrospective and prospective analyses. In the retrospective cohort, SharkVNTyper identified 23 additional positive participants who were not suspected clinically and had been missed in the initial exome analysis; 18 of these participants were confirmed as carrying the\n MUC1<\/jats:italic>\n 27dupC mutation by low-throughput Snapshot PCR. In the prospective cohort of 825 participants with CKD, systematic screening discovered 13 positive participants, with 12 confirmed by PCR. Overall, of 63 participants (1.4% of 4653) with molecularly confirmed ADTKD-\n MUC1<\/jats:italic>\n , comprehensive diagnoses and descriptions of the disease were available for 24 participants. The median age of kidney failure was 50 years, 38% exhibited bilateral multiple kidney cysts, 8% had early-onset gout, and 58% had arterial hypertension.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n SharkVNTyper enabled the analysis of highly repeated regions, such as the\n MUC1<\/jats:italic>\n VNTR, and facilitated the systematic screening of ADTKD-\n MUC1<\/jats:italic>\n from exome data, fostering 27dupC variation identification.\n <\/jats:p>\n <\/jats:sec>\n \n Podcast<\/jats:title>\n This article contains a podcast at https:\/\/dts.podtrac.com\/redirect.mp3\/www.asn-online.org\/media\/podcast\/JASN\/2024_11_15_KTS_November2024.mp3<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000503","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T12:07:58Z","timestamp":1727352478000},"page":"256-263","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":14,"title":["Systematic Screening of Autosomal Dominant Tubulointerstitial Kidney Disease\u2013MUC1 27dupC Pathogenic Variant through Exome Sequencing"],"prefix":"10.1681","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4788-7974","authenticated-orcid":false,"given":"Ilias","family":"Bensouna","sequence":"first","affiliation":[{"name":"Soins Intensifs N\u00e9phrologiques et Rein Aigu (SINRA), Nephrology Department, Tenon Hospital, Assistance Publique \u2013 H\u00f4pitaux de Paris, Paris, France"},{"name":"Inserm UMR_S1155, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-0913","authenticated-orcid":false,"given":"Thomas","family":"Robert","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Center, Assistance publique-H\u00f4pitaux de Marseille, La Conception Hospital, Marseille, France"},{"name":"Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8875-5851","authenticated-orcid":false,"given":"Xavier","family":"Vanhoye","sequence":"additional","affiliation":[{"name":"Eurofins Biomnis Laboratory, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Dancer","sequence":"additional","affiliation":[{"name":"Eurofins Biomnis Laboratory, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Raymond","sequence":"additional","affiliation":[{"name":"Eurofins Biomnis Laboratory, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4943-2106","authenticated-orcid":false,"given":"Pierre","family":"Delaug\u00e8re","sequence":"additional","affiliation":[{"name":"ISCD, Maison des Mod\u00e9lisations Ing\u00e9nieries et Technologies, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-4538","authenticated-orcid":false,"given":"Pascale","family":"Hilbert","sequence":"additional","affiliation":[{"name":"Center of Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7776-1340","authenticated-orcid":false,"given":"Hugues","family":"Richard","sequence":"additional","affiliation":[{"name":"UMR_7238 \u2013 Biologie Computationnelle et Quantitative, Sorbonne University, Paris, France"},{"name":"Genome Competence Center (MF1) \u2013 Robert Koch Institute, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-3757","authenticated-orcid":false,"given":"Laurent","family":"Mesnard","sequence":"additional","affiliation":[{"name":"Soins Intensifs N\u00e9phrologiques et Rein Aigu (SINRA), Nephrology Department, Tenon Hospital, Assistance Publique \u2013 H\u00f4pitaux de Paris, Paris, France"},{"name":"Inserm UMR_S1155, Paris, France"},{"name":"Centre Maladie Rare MAHREA, Tenon Hospital, Assistance Publique \u2013 H\u00f4pitaux de Paris, Paris, France"},{"name":"Medicine Faculty, Paris Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"issue":"6","key":"B1-20250203","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.kint.2017.06.013","article-title":"Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders","volume":"92","author":"Mallett","year":"2017","journal-title":"Kidney Int."},{"key":"B2-20250203","doi-asserted-by":"crossref","first-page":"821189","DOI":"10.3389\/fneur.2022.821189","article-title":"Uncovering essential tremor genetics: the promise of long-read 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