{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T08:04:27Z","timestamp":1761897867271,"version":"3.37.3"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007937","name":"Peking University","doi-asserted-by":"publisher","award":["2013-1-06"],"award-info":[{"award-number":["2013-1-06"]}],"id":[{"id":"10.13039\/501100007937","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010909","name":"Young Scientists Fund","doi-asserted-by":"publisher","award":["81801128"],"award-info":[{"award-number":["81801128"]}],"id":[{"id":"10.13039\/501100010909","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Germline mosaicisms could be inherited to offspring, which considered as <jats:italic>\u201c<\/jats:italic>de novo<jats:italic>\u201d<\/jats:italic> in most cases. Paternal germline <jats:italic>MECP2<\/jats:italic> mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on <jats:italic>MECP2<\/jats:italic> germline mosaicism in males, not only RTT fathers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Thirty-two fathers of RTT girls with <jats:italic>MECP2<\/jats:italic> pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten <jats:italic>MECP2<\/jats:italic> hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm <jats:italic>MECP2<\/jats:italic> mosaicisms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Nine fathers with RTT daughters (28.1%, 9\/32) were found to have <jats:italic>MECP2<\/jats:italic> mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with <jats:italic>MECP2<\/jats:italic> c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, <jats:italic>MECP2<\/jats:italic> mosaicism was found in 7 sperm samples (28.0%, 7\/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with <jats:italic>MECP2<\/jats:italic> germline mosaicisms were found with <jats:italic>MECP2<\/jats:italic> mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with <jats:italic>MECP2<\/jats:italic> germline mosaicisms. Additionally, there was no linear correlation between MAFs of <jats:italic>MECP2<\/jats:italic> mosaicisms and the age of males with germline <jats:italic>MECP2<\/jats:italic> mosaicisms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Germline <jats:italic>MECP2<\/jats:italic> mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as <jats:italic>\u201c<\/jats:italic>de novo<jats:italic>\u201d<\/jats:italic>, more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12916-023-02846-2","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T19:32:44Z","timestamp":1682019164000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males"],"prefix":"10.1186","volume":"21","author":[{"given":"Yongxin","family":"Wen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhua","family":"Bao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"issue":"4","key":"2846_CR1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1136\/jmedgenet-2013-101519","volume":"50","author":"CS Ku","year":"2013","unstructured":"Ku CS, Tan EK, Cooper DN. From the periphery to centre stage: de novo single nucleotide variants play a key role in human genetic disease. J Med Genet. 2013;50(4):203\u201311. https:\/\/doi.org\/10.1136\/jmedgenet-2013-101519.","journal-title":"J Med Genet"},{"issue":"8","key":"2846_CR2","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/nrg3241","volume":"13","author":"JA Veltman","year":"2012","unstructured":"Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13(8):565\u201375. https:\/\/doi.org\/10.1038\/nrg3241.","journal-title":"Nat Rev Genet"},{"issue":"12","key":"2846_CR3","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.ejmg.2012.08.009","volume":"55","author":"X Zhang","year":"2012","unstructured":"Zhang X, Bao X, Zhang J, et al. Molecular characteristics of Chinese patients with Rett syndrome. Eur J Med Genet. 2012;55(12):677\u201381. https:\/\/doi.org\/10.1016\/j.ejmg.2012.08.009.","journal-title":"Eur J Med Genet"},{"issue":"5","key":"2846_CR4","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1086\/320109","volume":"68","author":"R Trappe","year":"2001","unstructured":"Trappe R, Laccone F, Cobilanschi J, et al. MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet. 2001;68(5):1093\u2013101. https:\/\/doi.org\/10.1086\/320109.","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2846_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3760\/cma.j.issn.1003-9406.2014.01.001","volume":"31","author":"X Zhang","year":"2014","unstructured":"Zhang X, Zhao Y, Bao X, et al. Genetic features and mechanism of Rett syndrome in Chinese population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014;31(1):1\u20135. https:\/\/doi.org\/10.3760\/cma.j.issn.1003-9406.2014.01.001.","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"issue":"6","key":"2846_CR6","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1038\/s41436-018-0348-2","volume":"21","author":"Q Zhang","year":"2019","unstructured":"Zhang Q, Yang X, Wang J, et al. Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort. Genet Med. 2019;21(6):1330\u20138. https:\/\/doi.org\/10.1038\/s41436-018-0348-2.","journal-title":"Genet Med"},{"issue":"4","key":"2846_CR7","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1111\/j.1399-0004.2006.00691.x","volume":"70","author":"JC Evans","year":"2006","unstructured":"Evans JC, Archer HL, Whatley SD, et al. Germline mosaicism for a MECP2 mutation in a man with two Rett daughters. Clin Genet. 2006;70(4):336\u20138. https:\/\/doi.org\/10.1111\/j.1399-0004.2006.00691.x.","journal-title":"Clin Genet"},{"issue":"8","key":"2846_CR8","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1038\/sj.ejhg.5201835","volume":"15","author":"M Venancio","year":"2007","unstructured":"Venancio M, Santos M, Pereira SA, et al. An explanation for another familial case of Rett syndrome: maternal germline mosaicism. Eur J Hum Genet. 2007;15(8):902\u20134. https:\/\/doi.org\/10.1038\/sj.ejhg.5201835.","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2846_CR9","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/ajmg.b.32534","volume":"174","author":"Q Zhang","year":"2017","unstructured":"Zhang Q, Zhao Y, Bao X, et al. Familial cases and male cases with MECP2 mutations. Am J Med Genet B Neuropsychiatr Genet. 2017;174(4):451\u20137. https:\/\/doi.org\/10.1002\/ajmg.b.32534.","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"2846_CR10","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1146\/annurev-genom-083115-022656","volume":"17","author":"N Arnheim","year":"2016","unstructured":"Arnheim N, Calabrese P. Germline stem cell competition, mutation hot spots, genetic disorders, and older fathers. Annu Rev Genomics Hum Genet. 2016;17:219\u201343. https:\/\/doi.org\/10.1146\/annurev-genom-083115-022656.","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"2","key":"2846_CR11","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.ajhg.2011.12.017","volume":"90","author":"A Goriely","year":"2012","unstructured":"Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet. 2012;90(2):175\u2013200. https:\/\/doi.org\/10.1016\/j.ajhg.2011.12.017.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"2846_CR12","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/cge.13790","volume":"98","author":"Y Wen","year":"2020","unstructured":"Wen Y, Wang J, Zhang Q, et al. MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort. Clin Genet. 2020;98(3):240\u201350. https:\/\/doi.org\/10.1111\/cge.13790.","journal-title":"Clin Genet"},{"issue":"8","key":"2846_CR13","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1002\/humu.23263","volume":"38","author":"R Krishnaraj","year":"2017","unstructured":"Krishnaraj R, Ho G, Christodoulou J. RettBASE: Rett syndrome database update. Hum Mutat. 2017;38(8):922\u201331. https:\/\/doi.org\/10.1002\/humu.23263.","journal-title":"Hum Mutat"},{"issue":"7","key":"2846_CR14","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/ng.862","volume":"43","author":"DF Conrad","year":"2011","unstructured":"Conrad DF, Keebler JE, DePristo MA, et al. Variation in genome-wide mutation rates within and between human families. Nat Genet. 2011;43(7):712\u20134. https:\/\/doi.org\/10.1038\/ng.862.","journal-title":"Nat Genet"},{"issue":"7412","key":"2846_CR15","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/nature11396","volume":"488","author":"A Kong","year":"2012","unstructured":"Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father\u2019s age to disease risk. Nature. 2012;488(7412):471\u20135. https:\/\/doi.org\/10.1038\/nature11396.","journal-title":"Nature"},{"issue":"10","key":"2846_CR16","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.tig.2013.04.005","volume":"29","author":"CD Campbell","year":"2013","unstructured":"Campbell CD, Eichler EE. Properties and rates of germline mutations in humans. Trends Genet. 2013;29(10):575\u201384. https:\/\/doi.org\/10.1016\/j.tig.2013.04.005.","journal-title":"Trends Genet"},{"issue":"3","key":"2846_CR17","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s10803-013-1902-z","volume":"44","author":"B Suter","year":"2014","unstructured":"Suter B, Treadwell-Deering D, Zoghbi HY, et al. Brief report: MECP2 mutations in people without Rett syndrome. J Autism Dev Disord. 2014;44(3):703\u201311. https:\/\/doi.org\/10.1007\/s10803-013-1902-z.","journal-title":"J Autism Dev Disord"},{"issue":"1\u20136","key":"2846_CR18","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1023\/A:1017074823337","volume":"102\u2013103","author":"SP Otto","year":"1998","unstructured":"Otto SP, Hastings IM. Mutation and selection within the individual. Genetica. 1998;102\u2013103(1\u20136):507\u201324.","journal-title":"Genetica"},{"issue":"18","key":"2846_CR19","doi-asserted-by":"publisher","first-page":"4772","DOI":"10.1016\/j.cell.2021.07.024","volume":"184","author":"X Yang","year":"2021","unstructured":"Yang X, Breuss MW, Xu X, et al. Developmental and temporal characteristics of clonal sperm mosaicism. Cell. 2021;184(18):4772-83 e15. https:\/\/doi.org\/10.1016\/j.cell.2021.07.024.","journal-title":"Cell"},{"issue":"10","key":"2846_CR20","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.tig.2021.05.007","volume":"37","author":"MW Breuss","year":"2021","unstructured":"Breuss MW, Yang X, Gleeson JG. Sperm mosaicism: implications for genomic diversity and disease. Trends Genet. 2021;37(10):890\u2013902. https:\/\/doi.org\/10.1016\/j.tig.2021.05.007.","journal-title":"Trends Genet"},{"issue":"5633","key":"2846_CR21","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1126\/science.1085710","volume":"301","author":"A Goriely","year":"2003","unstructured":"Goriely A, McVean GA, Rojmyr M, et al. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science. 2003;301(5633):643\u20136. https:\/\/doi.org\/10.1126\/science.1085710.","journal-title":"Science"},{"issue":"4","key":"2846_CR22","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1086\/378419","volume":"73","author":"RL Glaser","year":"2003","unstructured":"Glaser RL, Broman KW, Schulman RL, et al. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet. 2003;73(4):939\u201347. https:\/\/doi.org\/10.1086\/378419.","journal-title":"Am J Hum Genet"},{"issue":"6","key":"2846_CR23","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2015.05.015","volume":"161","author":"F Guo","year":"2015","unstructured":"Guo F, Yan L, Guo H, et al. The Transcriptome and DNA Methylome landscapes of human primordial germ cells. Cell. 2015;161(6):1437\u201352. https:\/\/doi.org\/10.1016\/j.cell.2015.05.015.","journal-title":"Cell"},{"issue":"3","key":"2846_CR24","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/BF01233363","volume":"16","author":"DJ Driscoll","year":"1990","unstructured":"Driscoll DJ, Migeon BR. Sex difference in methylation of single-copy genes in human meiotic germ cells: implications for X chromosome inactivation, parental imprinting, and origin of CpG mutations. Somat Cell Mol Genet. 1990;16(3):267\u201382. https:\/\/doi.org\/10.1007\/BF01233363.","journal-title":"Somat Cell Mol Genet"},{"key":"2846_CR25","doi-asserted-by":"publisher","unstructured":"Sasani TA, Pedersen BS, Gao Z, et al. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. Elife 2019;8 https:\/\/doi.org\/10.7554\/eLife.46922","DOI":"10.7554\/eLife.46922"},{"issue":"2","key":"2846_CR26","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ajhg.2014.07.003","volume":"95","author":"IM Campbell","year":"2014","unstructured":"Campbell IM, Yuan B, Robberecht C, et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet. 2014;95(2):173\u201382. https:\/\/doi.org\/10.1016\/j.ajhg.2014.07.003.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"2846_CR27","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.ajhg.2017.07.016","volume":"101","author":"DR Krupp","year":"2017","unstructured":"Krupp DR, Barnard RA, Duffourd Y, et al. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am J Hum Genet. 2017;101(3):369\u201390. https:\/\/doi.org\/10.1016\/j.ajhg.2017.07.016.","journal-title":"Am J Hum Genet"},{"issue":"8","key":"2846_CR28","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1002\/humu.23255","volume":"38","author":"Y Dou","year":"2017","unstructured":"Dou Y, Yang X, Li Z, et al. Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations. Hum Mutat. 2017;38(8):1002\u201313. https:\/\/doi.org\/10.1002\/humu.23255.","journal-title":"Hum Mutat"},{"issue":"7367","key":"2846_CR29","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature10423","volume":"478","author":"H Najmabadi","year":"2011","unstructured":"Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478(7367):57\u201363. https:\/\/doi.org\/10.1038\/nature10423.","journal-title":"Nature"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-023-02846-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-023-02846-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-023-02846-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T19:35:03Z","timestamp":1682019303000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedicine.biomedcentral.com\/articles\/10.1186\/s12916-023-02846-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,20]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["2846"],"URL":"https:\/\/doi.org\/10.1186\/s12916-023-02846-2","relation":{},"ISSN":["1741-7015"],"issn-type":[{"type":"electronic","value":"1741-7015"}],"subject":[],"published":{"date-parts":[[2023,4,20]]},"assertion":[{"value":"9 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study procedures were approved by the Institutional Review Board at Peking University and the Ethics Committee of Peking University First Hospital under approval code IRB00001052-11087. All recruited patients provided written informed consent upon enrollment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"155"}}