{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:24:19Z","timestamp":1786980259739,"version":"build-2736575974"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["No. P3-0054"],"award-info":[{"award-number":["No. P3-0054"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Nephrol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alport kidney disease (AKD) presents one of the most prevalent genetic kidney disorders, characterized by a complex genetic background and diverse clinical manifestations. This study aimed to review the clinical and genetic features of pediatric patients with\n                      <jats:italic>COL4A3\u20135<\/jats:italic>\n                      variants and identify novel genetic variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Data were collected retrospectively at a national level from pediatric patients up to 19 years old, who underwent genetic testing between 2008 and 2023. Patients with pathogenic and likely pathogenic\n                      <jats:italic>COL4A3\u20135<\/jats:italic>\n                      variants were included. Their clinical, laboratory, and genetic characteristics were presented.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Over 15 years, 85 children and adolescents tested positive for pathogenic or likely pathogenic\n                      <jats:italic>COL4A3\u20135<\/jats:italic>\n                      variants. Increasing incidence was noted as genetic testing became more prevalent. One patient (1.2%) progressed to kidney failure and six (7%) had extrarenal involvement. Pathogenic or likely pathogenic variants in\n                      <jats:italic>COL4A3<\/jats:italic>\n                      ,\n                      <jats:italic>COL4A4<\/jats:italic>\n                      , and\n                      <jats:italic>COL4A5<\/jats:italic>\n                      genes were found in 14 (16.4%), 34 (40.0%), and 37 (43.6%) patients, respectively. Patients were diagnosed with autosomal, X-linked, and digenic AKD in 55.2%, 43.6%, and 1.2%, respectively. Eight novel variants were recorded, and their associated phenotype presented.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study expands the genetic and clinical background of pediatric patients with AKD, presenting on a spectrum from mild hematuria to progressive chronic kidney disease. Genetic confirmation and risk stratification in the pediatric population are critical to ensure timely care and potentially slow down the progression of kidney disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00467-025-06683-8","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:47:58Z","timestamp":1738741678000},"page":"2215-2223","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A 15-year experience highlighting the spectrum of Alport kidney disease in the pediatric population and novel genetic variants in COL4A3\u20135"],"prefix":"10.1007","volume":"40","author":[{"given":"Nastja","family":"Andreja\u0161i\u010d","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6170-1412","authenticated-orcid":false,"given":"Anja","family":"Blejc Novak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Mo\u010dnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nata\u0161a","family":"Mar\u010dun Varda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0160pela","family":"Stangler Herode\u017e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijela","family":"Krgovi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrej","family":"Zupan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anamarija","family":"Megli\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"6683_CR1","doi-asserted-by":"publisher","unstructured":"Pedrosa AL, Bitencourt L, Paranhos RM, Leit\u00e1o CA, Ferreira GC, Sim\u00f5es E Silva AC (2021) Alport syndrome: a comprehensive review on genetics, pathophysiology, histology, clinical and therapeutic perspectives. Curr Med Chem 28:5602\u20135624. https:\/\/doi.org\/10.2174\/0929867328666210108113500","DOI":"10.2174\/0929867328666210108113500"},{"key":"6683_CR2","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1053\/j.ajkd.2020.03.026","volume":"77","author":"CE Kashtan","year":"2021","unstructured":"Kashtan CE (2021) Alport syndrome: achieving early diagnosis and treatment. Am J Kidney Dis 77:272\u2013279. https:\/\/doi.org\/10.1053\/j.ajkd.2020.03.026","journal-title":"Am J Kidney Dis"},{"key":"6683_CR3","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1053\/j.ajkd.2024.04.021","volume":"84","author":"M Blasco","year":"2024","unstructured":"Blasco M, Quiroga B, Garc\u00eda-Aznar JM, Castro-Alonso C, Fern\u00e1ndez-Granados SJ, Luna E, Fern\u00e1ndez Fresnedo G, Ossorio M, Izquierdo MJ, Sanchez-Ospina D, Casta\u00f1eda-Infante L, Mouzo R, Cao M, Besada-Cerecedo ML, Pan-Lizcano R, Torra R, Ortiz A, De Sequera P (2024) Genetic characterization of kidney failure of unknown etiology in Spain: findings from the GENSEN study. Am J Kidney Dis 84:719-730.e1. https:\/\/doi.org\/10.1053\/j.ajkd.2024.04.021","journal-title":"Am J Kidney Dis"},{"key":"6683_CR4","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/s41431-022-01075-0","volume":"30","author":"S Daga","year":"2022","unstructured":"Daga S, Ding J, Deltas C, Savige J, Lipska-Zi\u0119tkiewicz BS, Hoefele J, Flinter F, Gale DP, Aksenova M, Kai H, Perin L, Barua M, Torra R, Miner JH, Massella L, Ljubanovi\u0107 DG, Lennon R, Weinstock AB, Knebelmann B, Cerkauskaite A, Gear S, Gross O, Turner AN, Baldassarri M, Pinto AM, Renieri A (2022) The 2019 and 2021 international workshops on Alport syndrome. Eur J Hum Genet 30:507\u2013516. https:\/\/doi.org\/10.1038\/s41431-022-01075-0","journal-title":"Eur J Hum Genet"},{"key":"6683_CR5","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/ajmg.c.31987","volume":"190","author":"CE Kashtan","year":"2022","unstructured":"Kashtan CE (2022) Genetic testing and glomerular hematuria\u2014a nephrologist\u2019s perspective. Am J Med Genet C Semin Med Genet 190:399\u2013403. https:\/\/doi.org\/10.1002\/ajmg.c.31987","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"6683_CR6","doi-asserted-by":"publisher","unstructured":"Savige J, Storey H, Watson E, Hertz JM, Deltas C, Renieri A, Mari F, Hilbert P, Plevova P, Byers P, Cerkauskaite A, Gregory M, Cerkauskiene R, Ljubanovic DG, Becherucci F, Errichiello C, Massella L, Aiello V, Lennon R, Hopkinson L, Koziell A, Lungu A, Rothe HM, Hoefele J, Zacchia M, Martic TN, Gupta A, Van Eerde A, Gear S, Landini S, Palazzo V, al-Rabadi L, Claes K, Corveleyn A, Van Hoof E, Van Geel M, Williams M, Ashton E, Belge H, Ars E, Bierzynska A, Gangemi C, Lipska-Zi\u0119tkiewicz BS (2021) Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet 29:1186\u20131197. https:\/\/doi.org\/10.1038\/s41431-021-00858-1","DOI":"10.1038\/s41431-021-00858-1"},{"key":"6683_CR7","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s00467-020-04819-6","volume":"36","author":"CE Kashtan","year":"2021","unstructured":"Kashtan CE, Gross O (2021) Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults\u2013an update for 2020. Pediatr Nephrol 36:711\u2013719. https:\/\/doi.org\/10.1007\/s00467-020-04819-6","journal-title":"Pediatr Nephrol"},{"key":"6683_CR8","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1097\/MNH.0000000000000983","volume":"33","author":"P Puapatanakul","year":"2024","unstructured":"Puapatanakul P, Miner JH (2024) Alport syndrome and Alport kidney diseases \u2013 elucidating the disease spectrum. Curr Opin Nephrol Hypertens 33:283\u2013290. https:\/\/doi.org\/10.1097\/MNH.0000000000000983","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"6683_CR9","doi-asserted-by":"publisher","first-page":"766224","DOI":"10.3389\/fmed.2021.766224","volume":"8","author":"X Zhou","year":"2021","unstructured":"Zhou X, Wang J, Mao J, Ye Q (2021) Clinical manifestations of Alport syndrome-diffuse leiomyomatosis patients with contiguous gene deletions in COL4A6 and COL4A5. Front Med 8:766224. https:\/\/doi.org\/10.3389\/fmed.2021.766224","journal-title":"Front Med"},{"key":"6683_CR10","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.kint.2017.12.018","volume":"93","author":"CE Kashtan","year":"2018","unstructured":"Kashtan CE, Ding J, Garosi G, Heidet L, Massella L, Nakanishi K, Nozu K, Renieri A, Rheault M, Wang F, Gross O (2018) Alport syndrome: a unified classification of genetic disorders of collagen IV \u03b1345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int 93:1045\u20131051. https:\/\/doi.org\/10.1016\/j.kint.2017.12.018","journal-title":"Kidney Int"},{"key":"6683_CR11","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1097\/00005792-199909000-00005","volume":"78","author":"CE Kashtan","year":"1999","unstructured":"Kashtan CE (1999) Alport syndrome: an inherited disorder of renal, ocular, and cochlear basement membranes. Medicine (Baltimore) 78:338\u2013360. https:\/\/doi.org\/10.1097\/00005792-199909000-00005","journal-title":"Medicine (Baltimore)"},{"key":"6683_CR12","doi-asserted-by":"publisher","unstructured":"Savige J, Lipska-Zietkiewicz BS, Watson E, Hertz JM, Deltas C, Mari F, Hilbert P, Plevova P, Byers P, Cerkauskaite A, Gregory M, Cerkauskiene R, Ljubanovic DG, Becherucci F, Errichiello C, Massella L, Aiello V, Lennon R, Hopkinson L, Koziell A, Lungu A, Rothe HM, Hoefele J, Zacchia M, Martic TN, Gupta A, Van Eerde A, Gear S, Landini S, Palazzo V, al-Rabadi L, Claes K, Corveleyn A, Van Hoof E, Van Geel M, Williams M, Ashton E, Belge H, Ars E, Bierzynska A, Gangemi C, Renieri A, Storey H, Flinter F (2022) Guidelines for genetic testing and management of Alport syndrome. Clin J Am Soc Nephrol 17:143\u2013154. https:\/\/doi.org\/10.2215\/CJN.04230321","DOI":"10.2215\/CJN.04230321"},{"key":"6683_CR13","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1093\/ndt\/gfv454","volume":"31","author":"H Pottel","year":"2016","unstructured":"Pottel H, Hoste L, Dubourg L, Ebert N, Schaeffner E, Eriksen BO, Melsom T, Lamb EJ, Rule AD, Turner ST, Glassock RJ, De Souza V, Selistre L, Mariat C, Martens F, Delanaye P (2016) An estimated glomerular filtration rate equation for the full age spectrum. Nephrol Dial Transplant 31:798\u2013806. https:\/\/doi.org\/10.1093\/ndt\/gfv454","journal-title":"Nephrol Dial Transplant"},{"key":"6683_CR14","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1038\/sj.ki.5002221","volume":"71","author":"M \u0160lajpah","year":"2007","unstructured":"\u0160lajpah M, Gorin\u0161ek B, Berginc G, Vizjak A, Ferluga D, Hvala A, Megli\u010d A, Jak\u0161a I, Furlan P, Gregori\u010d A, Kaplan-Pavlov\u010di\u010d \u0160, Ravnik-Glava\u010d M, Glava\u010d D (2007) Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int 71:1287\u20131295. https:\/\/doi.org\/10.1038\/sj.ki.5002221","journal-title":"Kidney Int"},{"key":"6683_CR15","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.3390\/genes11111377","volume":"11","author":"A Zupan","year":"2020","unstructured":"Zupan A, Matja\u0161i\u010d A, Grubelnik G, Tasi\u0107 V, Momirovska A (2020) Mutations in collagen genes in the context of an isolated population. Genes 11:1377. https:\/\/doi.org\/10.3390\/genes11111377","journal-title":"Genes"},{"key":"6683_CR16","doi-asserted-by":"publisher","first-page":"11063","DOI":"10.3390\/ijms222011063","volume":"22","author":"R Mart\u00ednez-Pulleiro","year":"2021","unstructured":"Mart\u00ednez-Pulleiro R, Garc\u00eda-Murias M, Fidalgo-D\u00edaz M, Garc\u00eda-Gonz\u00e1lez M\u00c1 (2021) Molecular basis, diagnostic challenges and therapeutic approaches of Alport syndrome: a primer for clinicians. Int J Mol Sci 22:11063. https:\/\/doi.org\/10.3390\/ijms222011063","journal-title":"Int J Mol Sci"},{"key":"6683_CR17","doi-asserted-by":"publisher","unstructured":"Gibson J, Fieldhouse R, Chan MMY, Sadeghi-Alavijeh O, Burnett L, Izzi V, Persikov AV, Gale DP, Storey H, Savige J, on behalf of the Genomics England Research Consortium (2021) Prevalence estimates of predicted pathogenic COL4A3\u2013COL4A5 variants in a population sequencing database and their implications for Alport syndrome. J Am Soc Nephrol 32:2273\u20132290. https:\/\/doi.org\/10.1681\/ASN.2020071065","DOI":"10.1681\/ASN.2020071065"},{"key":"6683_CR18","doi-asserted-by":"publisher","first-page":"3625","DOI":"10.1007\/s00467-023-05993-z","volume":"38","author":"MN Rheault","year":"2023","unstructured":"Rheault MN, McLaughlin HM, Mitchell A, Blake LE, Devarajan P, Warady BA, Gibson KL, Lieberman KV (2023) COL4A gene variants are common in children with hematuria and a family history of kidney disease. Pediatr Nephrol 38:3625\u20133633. https:\/\/doi.org\/10.1007\/s00467-023-05993-z","journal-title":"Pediatr Nephrol"},{"key":"6683_CR19","doi-asserted-by":"publisher","first-page":"e24","DOI":"10.1002\/humu.24480","volume":"43","author":"MH Al-Hamed","year":"2022","unstructured":"Al-Hamed MH, Hussein MH, Shah Y, Al-Mojalli H, Alsabban E, Alshareef T, Altayyar A, Elshouny S, Ali W, Abduljabbar M, AlOtaibi A, AlShammasi A, Akili R, Abouelhoda M, Sayer JA, Dasouki MJ, Imtiaz F (2022) Exome sequencing unravels genetic variants associated with chronic kidney disease in Saudi Arabian patients. Hum Mutat 43:e24\u2013e37. https:\/\/doi.org\/10.1002\/humu.24480","journal-title":"Hum Mutat"},{"key":"6683_CR20","doi-asserted-by":"publisher","unstructured":"Hora\u010dek M, Niku\u0161eva Marti\u0107 T, \u0160enjug P, \u0160enjug Perica M, Oroz M, Kuzmac S, Klari\u0107 D, Glavina Durdov M, Saraga M, Milo\u0161evi\u0107 D, Batini\u0107 D, \u0106ori\u0107 M, Pai\u0107 F, Gale\u0161i\u0107 Ljubanovi\u0107 D (2023) Clinical and histopathological characteristics of COL4A3 c.2881+1G>A variant causing Alport spectrum disorders in Croatian population. Biomol Biomed 23:89-100. https:\/\/doi.org\/10.17305\/bjbms.2022.7567","DOI":"10.17305\/bjbms.2022.7567"},{"key":"6683_CR21","doi-asserted-by":"publisher","first-page":"e76360","DOI":"10.1371\/journal.pone.0076360","volume":"8","author":"R Chatterjee","year":"2013","unstructured":"Chatterjee R, Hoffman M, Cliften P, Seshan S, Liapis H, Jain S (2013) Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria. PLoS One 8:e76360. https:\/\/doi.org\/10.1371\/journal.pone.0076360","journal-title":"PLoS One"},{"key":"6683_CR22","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.2215\/CJN.03120322","volume":"17","author":"J Savige","year":"2022","unstructured":"Savige J, Renieri A, Ars E, Daga S, Pinto AM, Rothe H, Gale DP, Aksenova M, Cerkauskaite A, Bielska O, Lipska-Zietkiewicz B, Gibson JT (2022) Digenic Alport syndrome. Clin J Am Soc Nephrol 17:1697\u20131706. https:\/\/doi.org\/10.2215\/CJN.03120322","journal-title":"Clin J Am Soc Nephrol"},{"key":"6683_CR23","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1007\/s00467-020-04574-8","volume":"35","author":"G Ozdemir","year":"2020","unstructured":"Ozdemir G, Gulhan B, Atayar E, Sayg\u0131l\u0131 S, Soylemezoglu O, Ozcakar ZB, Eroglu FK, Candan C, Demir BK, Soylu A, Y\u00fcksel S, Alpay H, Agbas A, Duzova A, Hayran M, Ozaltin F, Topaloglu R (2020) COL4A3 mutation is an independent risk factor for poor prognosis in children with Alport syndrome. Pediatr Nephrol 35:1941\u20131952. https:\/\/doi.org\/10.1007\/s00467-020-04574-8","journal-title":"Pediatr Nephrol"},{"key":"6683_CR24","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1186\/s12920-024-01953-0","volume":"17","author":"D Wang","year":"2024","unstructured":"Wang D, Pan M, Li H, Li M, Li P, Xiong F, Xiao H (2024) Four novel mutations identified in the COL4A3, COL4A4 and COL4A5 genes in 10 families with Alport syndrome. BMC Med Genomics 17:181. https:\/\/doi.org\/10.1186\/s12920-024-01953-0","journal-title":"BMC Med Genomics"},{"key":"6683_CR25","doi-asserted-by":"publisher","unstructured":"Zellers M, Solanki K, Kelly MA, Murphy KM, Retterer K, Kirchner HL, Bucaloiu ID, Moore B, Mirshahi T, Chang AR (2024) Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity of COL4A5 variants. medRxiv [Preprint]. 2024 Aug 9:2024.06.04.24308453. https:\/\/doi.org\/10.1101\/2024.06.04.24308453","DOI":"10.1101\/2024.06.04.24308453"}],"container-title":["Pediatric Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-025-06683-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00467-025-06683-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-025-06683-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:17:51Z","timestamp":1748323071000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00467-025-06683-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":25,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["6683"],"URL":"https:\/\/doi.org\/10.1007\/s00467-025-06683-8","relation":{},"ISSN":["0931-041X","1432-198X"],"issn-type":[{"value":"0931-041X","type":"print"},{"value":"1432-198X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,5]]},"assertion":[{"value":"26 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Commission of the Republic of Slovenia on Medical Ethics (0120-127\/2024-2711-4) and the Institutional Ethics Committee in Maribor (protocol code UKC-MB-KME-4\/24) approved the study. The study was performed in accordance with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent for the genetic analysis was obtained from all patients or their parents\/caregivers.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}