{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:37:15Z","timestamp":1777901835020,"version":"3.51.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hum Genet"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12\u201335% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in <jats:italic>TMEM260<\/jats:italic>; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in <jats:italic>GATA6<\/jats:italic>, and in another patient, we identified a de novo probably pathogenic variant in <jats:italic>NOTCH1<\/jats:italic>. Notably, we identified a prevalent variant in <jats:italic>TMEM260<\/jats:italic> (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8\/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights <jats:italic>TMEM260<\/jats:italic>, especially c.1617del, as a major genetic cause of TA in the Japanese population.<\/jats:p>","DOI":"10.1038\/s10038-024-01223-y","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T07:02:53Z","timestamp":1707807773000},"page":"177-183","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population"],"prefix":"10.1038","volume":"69","author":[{"given":"Hisao","family":"Yaoita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiichiro","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Takayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Iwasawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoya","family":"Saijo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Abiko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouta","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gen","family":"Tamiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeo","family":"Kure","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1002-8739","authenticated-orcid":false,"given":"Atsuo","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"key":"1223_CR1","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1161\/CIRCRESAHA.116.309140","volume":"120","author":"S Zaidi","year":"2017","unstructured":"Zaidi S, Brueckner M. Genetics and genomics of congenital heart disease. Circ Res. 2017;120:923\u201340.","journal-title":"Circ Res"},{"key":"1223_CR2","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1016\/j.athoracsur.2020.06.036","volume":"111","author":"PS Naimo","year":"2021","unstructured":"Naimo PS, Konstantinov IE. Surgery for truncus arteriosus: contemporary practice. Ann Thorac Surg. 2021;111:1442\u201350.","journal-title":"Ann Thorac Surg"},{"key":"1223_CR3","doi-asserted-by":"publisher","first-page":"e653","DOI":"10.1161\/CIR.0000000000000606","volume":"138","author":"ME Pierpont","year":"2018","unstructured":"Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, et al. Genetic basis for congenital heart disease: revisited: a scientific statement from the american heart association. Circulation. 2018;138:e653\u2013711.","journal-title":"Circulation"},{"key":"1223_CR4","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1016\/S0140-6736(03)14632-6","volume":"362","author":"H Yagi","year":"2003","unstructured":"Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366\u201373.","journal-title":"Lancet"},{"key":"1223_CR5","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1111\/cge.12835","volume":"91","author":"W Su","year":"2017","unstructured":"Su W, Zhu P, Wang R, Wu Q, Wang M, Zhang X, et al. Congenital heart diseases and their association with the variant distribution features on susceptibility genes. Clin Genet. 2017;91:349\u201354.","journal-title":"Clin Genet"},{"key":"1223_CR6","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1136\/jmedgenet-2013-102100","volume":"51","author":"A Ta-Shma","year":"2014","unstructured":"Ta-Shma A, El-lahham N, Edvardson S, Stepensky P, Nir A, Perles Z, et al. Conotruncal malformations and absent thymus due to a deleterious NKX2-6 mutation. J Med Genet. 2014;51:268\u201370.","journal-title":"J Med Genet"},{"key":"1223_CR7","doi-asserted-by":"publisher","first-page":"13933","DOI":"10.1073\/pnas.0904744106","volume":"106","author":"K Kodo","year":"2009","unstructured":"Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, et al. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci USA. 2009;106:13933\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1223_CR8","doi-asserted-by":"publisher","first-page":"e2302584120","DOI":"10.1073\/pnas.2302584120","volume":"120","author":"ISB Larsen","year":"2023","unstructured":"Larsen ISB, Povolo L, Zhou L, Tian W, Mygind KJ, Hintze J, et al. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proc Natl Acad Sci USA. 2023;120:e2302584120.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1223_CR9","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.ajhg.2017.02.007","volume":"100","author":"A Ta-Shma","year":"2017","unstructured":"Ta-Shma A, Khan TN, Vivante A, Willer JR, Matak P, Jalas C, et al. Mutations in TMEM260 cause a pediatric neurodevelopmental, cardiac, and renal syndrome. Am J Hum Genet. 2017;100:666\u201375.","journal-title":"Am J Hum Genet"},{"key":"1223_CR10","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63245","author":"Y Kuroda","year":"2023","unstructured":"Kuroda Y, Saito Y, Enomoto Y, Naruto T, Mitsui J, Kurosawa K. PHACES-like syndrome with TMEM260 compound heterozygous variants. Am J Med Genet A. 2023. https:\/\/doi.org\/10.1002\/ajmg.a.63245.","journal-title":"Am J Med Genet A"},{"key":"1223_CR11","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1111\/cge.14071","volume":"101","author":"AT Pagnamenta","year":"2022","unstructured":"Pagnamenta AT, Jackson A, Perveen R, Beaman G, Petts G, Gupta A, et al. Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects. Clin Genet. 2022;101:127\u201333.","journal-title":"Clin Genet"},{"key":"1223_CR12","doi-asserted-by":"publisher","first-page":"1157042","DOI":"10.3389\/fmed.2023.1157042","volume":"10","author":"M Peng","year":"2023","unstructured":"Peng M, Jing S, Duan S, Lu G, Zhou K, Hua Y, et al. A novel homozygous variant of TMEM260 induced cardiac malformation and neurodevelopmental abnormality: case report and literature review. Front Med. 2023;10:1157042.","journal-title":"Front Med"},{"key":"1223_CR13","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-022-01392-w","author":"A Saito-Hakoda","year":"2022","unstructured":"Saito-Hakoda A, Kikuchi A, Takahashi T, Yokoyama Y, Himori N, Adachi M, et al. Familial Paget\u2019s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27). J Bone Min Metab. 2022. https:\/\/doi.org\/10.1007\/s00774-022-01392-w. Available from","journal-title":"J Bone Min Metab"},{"key":"1223_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-020-20146-8","volume":"12","author":"J Takayama","year":"2021","unstructured":"Takayama J, Tadaka S, Yano K, Katsuoka F, Gocho C, Funayama T, et al. Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference. Nat Commun. 2021;12:1\u201314.","journal-title":"Nat Commun"},{"key":"1223_CR15","doi-asserted-by":"publisher","DOI":"10.3791\/3321","author":"J Hui-Yuen","year":"2011","unstructured":"Hui-Yuen J, McAllister S, Koganti S, Hill E, Bhaduri-McIntosh S. Establishment of Epstein-Barr virus growth-transformed lymphoblastoid cell lines. J Vis Exp. 2011. https:\/\/doi.org\/10.3791\/3321.","journal-title":"J Vis Exp"},{"key":"1223_CR16","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343.","journal-title":"Nature"},{"key":"1223_CR17","doi-asserted-by":"publisher","first-page":"D536","DOI":"10.1093\/nar\/gkaa1034","volume":"49","author":"S Tadaka","year":"2020","unstructured":"Tadaka S, Hishinuma E, Komaki S, Motoike IN, Kawashima J, Saigusa D, et al. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. Nucleic Acids Res. 2020;49:D536\u201344.","journal-title":"Nucleic Acids Res"},{"key":"1223_CR18","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/s41422-020-0322-9","volume":"30","author":"Y Cao","year":"2020","unstructured":"Cao Y, Li L, Xu M, Feng Z, Sun X, Lu J, et al. The ChinaMAP analytics of deep whole genome sequences in 10,588 individuals. Cell Res. 2020;30:717\u201331.","journal-title":"Cell Res"},{"key":"1223_CR19","doi-asserted-by":"publisher","first-page":"100197","DOI":"10.1016\/j.xgen.2022.100197","volume":"2","author":"Y-CA Feng","year":"2022","unstructured":"Feng Y-CA, Chen C-Y, Chen T-T, Kuo P-H, Hsu Y-H, Yang H-I, et al. Taiwan Biobank: a rich biomedical research database of the Taiwanese population. Cell Genom. 2022;2:100197.","journal-title":"Cell Genom"},{"key":"1223_CR20","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1038\/s12276-022-00871-4","volume":"54","author":"J Lee","year":"2022","unstructured":"Lee J, Lee J, Jeon S, Lee J, Jang I, Yang JO, et al. A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population. Exp Mol Med. 2022;54:1862\u201371.","journal-title":"Exp Mol Med"},{"key":"1223_CR21","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1111\/cge.14060","volume":"100","author":"V Shotelersuk","year":"2021","unstructured":"Shotelersuk V, Wichadakul D, Ngamphiw C, Srichomthong C, Phokaew C, Wilantho A, et al. The Thai reference exome (T-REx) variant database. Clin Genet. 2021;100:703\u201312.","journal-title":"Clin Genet"},{"key":"1223_CR22","doi-asserted-by":"publisher","first-page":"e3000586","DOI":"10.1371\/journal.pbio.3000586","volume":"18","author":"PK Albers","year":"2020","unstructured":"Albers PK, McVean G. Dating genomic variants and shared ancestry in population-scale sequencing data. PLoS Biol. 2020;18:e3000586.","journal-title":"PLoS Biol"},{"key":"1223_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41439-019-0059-5","volume":"6","author":"S Tadaka","year":"2019","unstructured":"Tadaka S, Katsuoka F, Ueki M, Makino S, Saito S, Otsuki A, et al. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. Hum Genome Var. 2019;6:1\u20139.","journal-title":"Hum Genome Var"},{"key":"1223_CR24","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/16915","volume":"397","author":"A Eyre-Walker","year":"1999","unstructured":"Eyre-Walker A, Keightley PD. High genomic deleterious mutation rates in hominids. Nature. 1999;397:344\u20137.","journal-title":"Nature"},{"key":"1223_CR25","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1093\/oxfordjournals.molbev.a003795","volume":"18","author":"N Yu","year":"2001","unstructured":"Yu N, Zhao Z, Fu YX, Sambuughin N, Ramsay M, Jenkins T, et al. Global patterns of human DNA sequence variation in a 10-kb region on chromosome 1. Mol Biol Evol. 2001;18:214\u201322.","journal-title":"Mol Biol Evol"},{"key":"1223_CR26","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S0378-1119(97)00398-3","volume":"205","author":"R Ophir","year":"1997","unstructured":"Ophir R, Graur D. Patterns and rates of indel evolution in processed pseudogenes from humans and murids. Gene. 1997;205:191\u2013202.","journal-title":"Gene"},{"key":"1223_CR27","doi-asserted-by":"publisher","first-page":"e8650","DOI":"10.1371\/journal.pone.0008650","volume":"5","author":"P Sj\u00f6din","year":"2010","unstructured":"Sj\u00f6din P, Bataillon T, Schierup MH. Insertion and deletion processes in recent human history. PLoS One. 2010;5:e8650.","journal-title":"PLoS One"},{"key":"1223_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/ng.1035","volume":"44","author":"HL Allen","year":"2011","unstructured":"Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2011;44:20\u20132.","journal-title":"Nat Genet"},{"key":"1223_CR29","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1161\/CIRCRESAHA.118.313250","volume":"124","author":"DJ Page","year":"2019","unstructured":"Page DJ, Miossec MJ, Williams SG, Monaghan RM, Fotiou E, Cordell HJ, et al. Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of fallot. Circ Res. 2019;124:553\u201363.","journal-title":"Circ Res"},{"key":"1223_CR30","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/ajmg.a.61294","volume":"179","author":"D \u0160kori\u0107-Milosavljevi\u0107","year":"2019","unstructured":"\u0160kori\u0107-Milosavljevi\u0107 D, Tjong FVY, Barc J, Backx APCM, Clur S-AB, van Spaendonck-Zwarts K, et al. GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum. Am J Med Genet A. 2019;179:1836\u201345.","journal-title":"Am J Med Genet A"}],"updated-by":[{"DOI":"10.1038\/s10038-024-01245-6","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000}}],"container-title":["Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s10038-024-01223-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-024-01223-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s10038-024-01223-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T03:17:01Z","timestamp":1723778221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s10038-024-01223-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["1223"],"URL":"https:\/\/doi.org\/10.1038\/s10038-024-01223-y","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s10038-024-01245-6","asserted-by":"object"}]},"ISSN":["1434-5161","1435-232X"],"issn-type":[{"value":"1434-5161","type":"print"},{"value":"1435-232X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,13]]},"assertion":[{"value":"23 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2024","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s10038-024-01245-6","URL":"https:\/\/doi.org\/10.1038\/s10038-024-01245-6","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Some of the authors declared Financial and Non-Financial Relationships and Activities, and Conflicts of Interest regarding this manuscript as indicated in the supplementary materials. The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}