{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:06:21Z","timestamp":1791371181841,"version":"4.3.1"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T00:00:00Z","timestamp":1600041600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T00:00:00Z","timestamp":1600041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020-MSCA-COFUND","doi-asserted-by":"publisher","award":["665403"],"award-info":[{"award-number":["665403"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["18671"],"award-info":[{"award-number":["18671"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Progetti per la ricerca oncologica della Regione Campania","award":["I-Cure"],"award-info":[{"award-number":["I-Cure"]}]},{"name":"Progetti competitivi intraAteneo\u201d Programma V:ALERE (VAnviteLli pEr la RicErca) 2019","award":["MIRIAM"],"award-info":[{"award-number":["MIRIAM"]}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP15131"],"award-info":[{"award-number":["GGP15131"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Epigenet"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of\n                      <jats:italic>PADI6<\/jats:italic>\n                      in infertility is well demonstrated, its role in imprinting disorders is less well established.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of\n                      <jats:italic>PADI6<\/jats:italic>\n                      variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our results firmly establish the role of\n                      <jats:italic>PADI6<\/jats:italic>\n                      in imprinting disorders. We report loss-of-function maternal-effect variants of\n                      <jats:italic>PADI6<\/jats:italic>\n                      that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte\n                      <jats:italic>PADI6<\/jats:italic>\n                      function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13148-020-00925-2","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T07:03:54Z","timestamp":1600067034000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance"],"prefix":"10.1186","volume":"12","author":[{"given":"Maria Vittoria","family":"Cubellis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pignata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Sparago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosita","family":"Del Prete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Monticelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Calzari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Antona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Melis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romano","family":"Tenconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-3021","authenticated-orcid":false,"given":"Flavia","family":"Cerrato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Riccio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,14]]},"reference":[{"key":"925_CR1","doi-asserted-by":"crossref","unstructured":"Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet. 2019;20(4):235\u201348.","DOI":"10.1038\/s41576-018-0092-0"},{"issue":"1","key":"925_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4274\/jcrpe.galenos.2019.2018.0249","volume":"12","author":"D Carli","year":"2020","unstructured":"Carli D, Riberi E, Ferrero GB, Mussa AJ. Syndromic disorders caused by disturbed human imprinting. Clin Res Pediatr Endocrinol. 2020;12(1):1\u201316.","journal-title":"Clin Res Pediatr Endocrinol"},{"issue":"10","key":"925_CR3","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1002\/ajmg.a.36080","volume":"161A","author":"A Mussa","year":"2013","unstructured":"Mussa A, Russo S, De Crescenzo A, Chiesa N, Molinatto C, Selicorni A, et al. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A. 2013;161A(10):2481\u20136.","journal-title":"Am J Med Genet A"},{"issue":"4","key":"925_CR4","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/nrendo.2017.166","volume":"14","author":"F Brioude","year":"2018","unstructured":"Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229\u201349.","journal-title":"Nat Rev Endocrinol"},{"issue":"7","key":"925_CR5","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.tig.2016.05.001","volume":"32","author":"M Sanchez-Delgado","year":"2016","unstructured":"Sanchez-Delgado M, Riccio A, Eggermann T, Maher ER, Lapunzina P, Mackay D, et al. Causes and consequences of multi-locus imprinting disturbances in humans. Trends Genet. 2016;32(7):444\u201355.","journal-title":"Trends Genet"},{"issue":"4","key":"925_CR6","doi-asserted-by":"publisher","first-page":"355","DOI":"10.3390\/genes11040355","volume":"11","author":"F Cerrato","year":"2020","unstructured":"Cerrato F, Sparago A, Ariani F, Brugnoletti F, Calzari L, Copped\u00e8 F, et al. DNA methylation in the diagnosis of monogenic diseases. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Genes. 2020;11(4):355.","journal-title":"Genes."},{"issue":"2","key":"925_CR7","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1093\/humupd\/dmz045","volume":"26","author":"M Elbracht","year":"2020","unstructured":"Elbracht M, Mackay D, Begemann M, Kagan KO, Eggermann T. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Hum Reprod Update. 2020;26(2):197\u2013213.","journal-title":"Hum Reprod Update"},{"issue":"8","key":"925_CR8","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/ng.187","volume":"40","author":"DJ Mackay","year":"2008","unstructured":"Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008;40(8):949\u201351.","journal-title":"Nat Genet"},{"issue":"11","key":"925_CR9","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.molmed.2017.09.004","volume":"23","author":"X Lu","year":"2017","unstructured":"Lu X, Gao Z, Qin D, Li L. a maternal functional module in the mammalian oocyte-to-embryo transition. Trends Mol Med. 2017;23(11):1014\u201323.","journal-title":"Trends Mol Med"},{"issue":"7","key":"925_CR10","doi-asserted-by":"publisher","first-page":"700","DOI":"10.2174\/1389450116666150202160954","volume":"16","author":"EE Witalison","year":"2015","unstructured":"Witalison EE, Thompson PR, Hofseth LJ. Protein arginine deiminases and associated citrullination: physiological functions and diseases associated with dysregulation. Curr Drug Targets. 2015;16(7):700\u201310.","journal-title":"Curr Drug Targets"},{"issue":"4","key":"925_CR11","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.jmb.2007.01.054","volume":"367","author":"R Raijmakers","year":"2007","unstructured":"Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, Soede-Huijbregts C, et al. Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. J Mol Biol. 2007;367(4):1118\u201329.","journal-title":"J Mol Biol"},{"issue":"3","key":"925_CR12","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.devcel.2008.07.010","volume":"15","author":"L Li","year":"2008","unstructured":"Li L, Baibakov B, Dean J. A subcortical maternal complex essential for preimplantation mouse embryogenesis. Dev Cell. 2008;15(3):416\u201325.","journal-title":"Dev Cell"},{"issue":"7","key":"925_CR13","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/s41431-018-0141-3","volume":"26","author":"J Qian","year":"2018","unstructured":"Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet. 2018;26(7):1007\u201313.","journal-title":"Eur J Hum Genet"},{"issue":"15","key":"925_CR14","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.1242\/dev.016329","volume":"135","author":"P Yurttas","year":"2008","unstructured":"Yurttas P, Vitale AM, Fitzhenry RJ, Cohen-Gould L, Wu W, Gossen JA, et al. Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Development. 2008;135(15):2627\u201336.","journal-title":"Development."},{"issue":"1-2","key":"925_CR15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.mce.2007.05.005","volume":"273","author":"G Esposito","year":"2007","unstructured":"Esposito G, Vitale AM, Leijten FP, Strik AM, Koonen-Reemst AM, Yurttas P, et al. Peptidylarginine deiminase (PAD) 6 is essential for oocyte cytoskeletal sheet formation and female fertility. Mol Cell Endocrinol. 2007;273(1-2):25\u201331.","journal-title":"Mol Cell Endocrinol"},{"issue":"3","key":"925_CR16","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.ajhg.2016.06.024","volume":"99","author":"Y Xu","year":"2016","unstructured":"Xu Y, Shi Y, Fu J, Yu M, Feng R, Sang Q, et al. Mutations in PADI6 cause female infertility characterized by early embryonic arrest. Am J Hum Genet. 2016;99(3):744\u201352.","journal-title":"Am J Hum Genet"},{"issue":"2","key":"925_CR17","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1111\/cge.12866","volume":"91","author":"S Maddirevula","year":"2017","unstructured":"Maddirevula S, Coskun S, Awartani K, Alsaif H, Abdulwahab FM, Alkuraya FS. The human knockout phenotype of PADI6 is female sterility caused by cleavage failure of their fertilized eggs. Clin Genet. 2017;91(2):344\u20135.","journal-title":"Clin Genet"},{"issue":"6","key":"925_CR18","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.rbmo.2018.03.009","volume":"36","author":"X Wang","year":"2018","unstructured":"Wang X, Song D, Mykytenko D, Kuang Y, Lv Q, Li B, et al. Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest. Reprod BioMed Online. 2018;36(6):698\u2013704.","journal-title":"Reprod BioMed Online"},{"issue":"1","key":"925_CR19","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10815-019-01606-7","volume":"37","author":"W Zheng","year":"2020","unstructured":"Zheng W, Chen L, Dai J, Dai C, Guo J, Lu C, et al. New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage. Assist Reprod Genet. 2020;37(1):205\u201312.","journal-title":"Assist Reprod Genet"},{"issue":"7","key":"925_CR20","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1136\/jmedgenet-2017-105190","volume":"55","author":"M Begemann","year":"2018","unstructured":"Begemann M, Rezwan FI, Beygo J, Docherty LE, Kolarova J, Schroeder C, et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. J Med Genet. 2018;55(7):497\u2013504.","journal-title":"J Med Genet"},{"issue":"3","key":"925_CR21","doi-asserted-by":"publisher","first-page":"e1000423","DOI":"10.1371\/journal.pgen.1000423","volume":"5","author":"E Meyer","year":"2009","unstructured":"Meyer E, Lim D, Pasha S, Tee LJ, Rahman F, Yates JR, et al. Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann syndrome). PLoS Genet. 2009;5(3):e1000423.","journal-title":"PLoS Genet"},{"issue":"1","key":"925_CR22","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1186\/s13148-019-0760-8","volume":"11","author":"A Sparago","year":"2019","unstructured":"Sparago A, Verma A, Patricelli MG, Pignata L, Russo S, Calzari L, et al. The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype. Clin Epigenetics. 2019;11(1):190.","journal-title":"Clin Epigenetics"},{"key":"925_CR23","doi-asserted-by":"publisher","first-page":"8086","DOI":"10.1038\/ncomms9086","volume":"6","author":"LE Docherty","year":"2015","unstructured":"Docherty LE, Rezwan FI, Poole RL, Turner CL, Kivuva E, Maher ER, et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat Commun. 2015;6:8086.","journal-title":"Nat Commun"},{"issue":"11","key":"925_CR24","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1038\/s41588-018-0232-7","volume":"50","author":"F Zink","year":"2018","unstructured":"Zink F, Magnusdottir DN, Magnusson OT, Walker NJ, Morris TJ, Sigurdsson A, et al. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes. Nat Genet. 2018;50(11):1542\u201352.","journal-title":"Nat Genet"},{"issue":"2","key":"925_CR25","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1080\/15592294.2016.1264561","volume":"13","author":"D Monk","year":"2018","unstructured":"Monk D, Morales J, den Dunnen JT, Russo S, Court F, Prawitt D, et al. Recommendations for a nomenclature system for reporting methylation aberrations in imprinted domains. Epigenetics. 2018;13(2):117\u201321.","journal-title":"Epigenetics."},{"issue":"6","key":"925_CR26","doi-asserted-by":"publisher","first-page":"e21314","DOI":"10.1371\/journal.pone.0021314","volume":"6","author":"YL Liu","year":"2011","unstructured":"Liu YL, Chiang YH, Liu GY, Hung HC. Functional role of dimerization of human peptidylarginine deiminase 4 (PAD4). PLoS One. 2011;6(6):e21314.","journal-title":"PLoS One"},{"issue":"11","key":"925_CR27","doi-asserted-by":"publisher","first-page":"3963","DOI":"10.1210\/jc.2015-2260","volume":"100","author":"B Bakker","year":"2015","unstructured":"Bakker B, Sonneveld LJ, Woltering MC, Bikker H, Kant SGJ. A girl with Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type 1b due to multiple imprinting defects. Clin Endocrinol Metab. 2015;100(11):3963\u20136.","journal-title":"Clin Endocrinol Metab"},{"issue":"8","key":"925_CR28","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1038\/jhg.2016.45","volume":"61","author":"S Sano","year":"2016","unstructured":"Sano S, Matsubara K, Nagasaki K, Kikuchi T, Nakabayashi K, Hata K, et al. Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon? Hum Genet. 2016;61(8):765\u20139.","journal-title":"Hum Genet"},{"issue":"5","key":"925_CR29","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/ejhg.2008.233","volume":"17","author":"J Bliek","year":"2009","unstructured":"Bliek J, Verde G, Callaway J, Maas SM, De Crescenzo A, Sparago A, et al. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2009;17(5):611\u20139.","journal-title":"Eur J Hum Genet"},{"issue":"2","key":"925_CR30","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/10409238.2019.1586828","volume":"54","author":"S Sharma","year":"2019","unstructured":"Sharma S, Schiller MR. The carboxy-terminus, a key regulator of protein function. Crit Rev Biochem Mol Biol. 2019;54(2):85\u2013102.","journal-title":"Crit Rev Biochem Mol Biol"},{"issue":"1","key":"925_CR31","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s13073-019-0694-y","volume":"11","author":"H Demond","year":"2019","unstructured":"Demond H, Anvar Z, Jahromi BN, Sparago A, Verma A, Davari M, et al. A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation. Genome Med. 2019;11(1):84.","journal-title":"Genome Med"},{"issue":"3","key":"925_CR32","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","volume":"16","author":"SA Miller","year":"1988","unstructured":"Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215. https:\/\/doi.org\/10.1093\/nar\/16.3.1215.","journal-title":"Nucleic Acids Res"},{"issue":"14","key":"925_CR33","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate short read alignment with BurrowsWheeler transform. Bioinformatics. 2009;25(14):1754\u201360.","journal-title":"Bioinformatics."},{"issue":"5","key":"925_CR34","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","volume":"43","author":"MA DePristo","year":"2011","unstructured":"DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491\u20138.","journal-title":"Nat Genet"},{"issue":"7","key":"925_CR35","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1136\/jmedgenet-2012-100918","volume":"49","author":"X Chang","year":"2012","unstructured":"Chang X, Wang K. wANNOVAR: annotating genetic variants for personal genomes via the web. J Med Genet. 2012;49(7):433\u20136.","journal-title":"J Med Genet"},{"issue":"7422","key":"925_CR36","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature11632","volume":"491","author":"C Genomes Project","year":"2012","unstructured":"Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56\u201365.","journal-title":"Nature."},{"issue":"7616","key":"925_CR37","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285\u201391.","journal-title":"Nature."},{"key":"925_CR38","doi-asserted-by":"publisher","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv. 2019:531210 https:\/\/doi.org\/10.1101\/531210.","DOI":"10.1101\/531210"},{"key":"925_CR39","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248\u20139.","journal-title":"Nat Methods"},{"key":"925_CR40","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s12859-018-2416-7","volume":"19","author":"C Cimmaruta","year":"2018","unstructured":"Cimmaruta C, Citro V, Andreotti G, Liguori L, Cubellis MV, Mele BH. Challenging popular tools for the annotation of genetic variations with a real case, pathogenic mutations of lysosomal alpha-galactosidase. BMC Bioinformatics. 2018;19:433.","journal-title":"BMC Bioinformatics"},{"key":"925_CR41","doi-asserted-by":"publisher","first-page":"W229","DOI":"10.1093\/nar\/gkx439","volume":"45","author":"AP Pandurangan","year":"2017","unstructured":"Pandurangan AP, Ochoa-Monta\u00f1o B, Ascher DB, Blundell TL. SDM: a server for predicting effects of mutations on protein stability. Nucleic Acids Res. 2017;45:W229\u201335.","journal-title":"Nucleic Acids Res"},{"key":"925_CR42","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","volume":"46","author":"A Waterhouse","year":"2018","unstructured":"Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. Swiss-model: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296\u2013303.","journal-title":"Nucleic Acids Res"},{"key":"925_CR43","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1021\/cb200258q","volume":"7","author":"JE Jones","year":"2012","unstructured":"Jones JE, Slack JL, Fang P, Zhang X, Subramanian V, Causey CP. Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem Biol. 2012;7:160\u20135.","journal-title":"ACS Chem Biol"},{"key":"925_CR44","doi-asserted-by":"crossref","unstructured":"Krissinel E, Henrick K. Inference of macromolecular assemblies from crystalline state. J Mol Biol. 2007;372:774\u201397.","DOI":"10.1016\/j.jmb.2007.05.022"}],"container-title":["Clinical Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-020-00925-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13148-020-00925-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13148-020-00925-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T04:19:08Z","timestamp":1696652348000},"score":1,"resource":{"primary":{"URL":"https:\/\/clinicalepigeneticsjournal.biomedcentral.com\/articles\/10.1186\/s13148-020-00925-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,14]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["925"],"URL":"https:\/\/doi.org\/10.1186\/s13148-020-00925-2","relation":{},"ISSN":["1868-7075","1868-7083"],"issn-type":[{"value":"1868-7075","type":"print"},{"value":"1868-7083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,14]]},"assertion":[{"value":"23 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Approval to conduct this study was obtained from the Ethical Committee of the University of Campania \u201cLuigi Vanvitelli\u201d together with the signed informed consent from parents of the individuals involved in this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication of clinical and molecular data was obtained from parents of the individuals involved in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no potential competing interests to disclose. The authors declare that they have no financial relationships relevant to this article to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"139"}}