{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T08:26:06Z","timestamp":1793780766619,"version":"4.6.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Legal Med"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Age estimation based on DNA methylation (DNAm) can be applied to children, adolescents and adults, but many CG dinucleotides (CpGs) exhibit different kinetics of age-associated DNAm across these age ranges. Furthermore, it is still unclear how growth disorders impact epigenetic age predictions, and this may be particularly relevant for a forensic application. In this study, we analyzed buccal mucosa samples from 95 healthy children and 104 children with different growth disorders. DNAm was analysed by pyrosequencing for 22 CpGs in the genes <jats:italic>PDE4C<\/jats:italic>, <jats:italic>ELOVL2<\/jats:italic>, <jats:italic>RPA2<\/jats:italic>, <jats:italic>EDARADD<\/jats:italic> and <jats:italic>DDO<\/jats:italic>. The relationship between DNAm and age in healthy children was tested by Spearman\u2019s rank correlation. Differences in DNAm between the groups \u201chealthy children\u201d and the (sub-)groups of children with growth disorders were tested by ANCOVA. Models for age estimation were trained (1) based on the data from 11 CpGs with a close correlation between DNAm and age (<jats:italic>R<\/jats:italic>\u2009\u2265\u20090.75) and (2) on five CpGs that also did not present significant differences in DNAm between healthy and diseased children. Statistical analysis revealed significant differences between the healthy group and the group with growth disorders (11 CpGs), the subgroup with a short stature (12 CpGs) and the non-short stature subgroup (three CpGs). The results are in line with the assumption of an epigenetic regulation of height-influencing genes. Age predictors trained on 11 CpGs with high correlations between DNAm and age revealed higher mean absolute errors (MAEs) in the group of growth disorders (mean MAE 2.21\u00a0years versus MAE 1.79 in the healthy group) as well as in the short stature (sub-)groups; furthermore, there was a clear tendency for overestimation of ages in all growth disorder groups (mean age deviations: total growth disorder group 1.85\u00a0years, short stature group 1.99\u00a0years). Age estimates on samples from children with growth disorders were more precise when using a model containing only the five CpGs that did not present significant differences in DNAm between healthy and diseased children (mean age deviations: total growth disorder group 1.45\u00a0years, short stature group 1.66\u00a0years). The results suggest that CpGs in genes involved in processes relevant for growth and development should be avoided in age prediction models for children since they may be sensitive for alterations in the DNAm pattern in cases of growth disorders.<\/jats:p>","DOI":"10.1007\/s00414-022-02826-w","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T13:04:16Z","timestamp":1652360656000},"page":"987-996","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Altered DNA methylation at age-associated CpG sites in children with growth disorders: impact on age estimation?"],"prefix":"10.1007","volume":"136","author":[{"given":"F.","family":"Mayer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Reinauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"B\u00f6hme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. B.","family":"Eickhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Koop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"G\u00fcnd\u00fcz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Ritz-Timme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"2826_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s00194-021-00490-9","author":"P B\u00f6hme","year":"2021","unstructured":"B\u00f6hme P, Reckert A, Becker J, Ritz-Timme S (2021) Molecular methods for age estimation. Rechtsmedizin. https:\/\/doi.org\/10.1007\/s00194-021-00490-9","journal-title":"Rechtsmedizin"},{"key":"2826_CR2","first-page":"121","volume":"29","author":"A Freire-Aradas","year":"2017","unstructured":"Freire-Aradas A, Phillips C, Lareu MV (2017) Forensic individual age estimation with DNA: From initial approaches to methylation tests. Forensic Sci Rev 29:121\u2013144","journal-title":"Forensic Sci Rev"},{"key":"2826_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/sdj.Sdj_27_20","volume":"5","author":"M Hanafi","year":"2021","unstructured":"Hanafi M, Soedarsono N, Auerkari E (2021) Biological age estimation using DNA methylation analysis: a systematic review. Sci Dent J 5:1\u201311. https:\/\/doi.org\/10.4103\/sdj.Sdj_27_20","journal-title":"Sci Dent J"},{"key":"2826_CR4","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12915-020-00807-2","volume":"18","author":"Y Han","year":"2020","unstructured":"Han Y, Franzen J, Stiehl T et al (2020) New targeted approaches for epigenetic age predictions. BMC Biol 18:71. https:\/\/doi.org\/10.1186\/s12915-020-00807-2","journal-title":"BMC Biol"},{"key":"2826_CR5","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1007\/s00414-020-02375-0","volume":"134","author":"BE Koop","year":"2020","unstructured":"Koop BE, Reckert A, Becker J, Han Y, Wagner W, Ritz-Timme S (2020) Epigenetic clocks may come out of rhythm-implications for the estimation of chronological age in forensic casework. Int J Legal Med 134:2215\u20132228. https:\/\/doi.org\/10.1007\/s00414-020-02375-0","journal-title":"Int J Legal Med"},{"key":"2826_CR6","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1007\/s00414-020-02263-7","volume":"134","author":"M Pfeifer","year":"2020","unstructured":"Pfeifer M, Bajanowski T, Helmus J, Poetsch M (2020) Inter-laboratory adaption of age estimation models by DNA methylation analysis-problems and solutions. Int J Legal Med 134:953\u2013961. https:\/\/doi.org\/10.1007\/s00414-020-02263-7","journal-title":"Int J Legal Med"},{"key":"2826_CR7","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.fsigen.2018.06.011","volume":"36","author":"A Freire-Aradas","year":"2018","unstructured":"Freire-Aradas A, Phillips C, Giron-Santamaria L et al (2018) Tracking age-correlated DNA methylation markers in the young. Forensic Sci Int Genet 36:50\u201359. https:\/\/doi.org\/10.1016\/j.fsigen.2018.06.011","journal-title":"Forensic Sci Int Genet"},{"key":"2826_CR8","doi-asserted-by":"publisher","unstructured":"Wu X, Chen W, Lin F et al (2019) DNA methylation profile is a quantitative measure of biological aging in children. Aging (Albany NY) 11: 10031\u201351. https:\/\/doi.org\/10.18632\/aging.102399","DOI":"10.18632\/aging.102399"},{"key":"2826_CR9","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1101\/gr.125187.111","volume":"22","author":"RS Alisch","year":"2012","unstructured":"Alisch RS, Barwick BG, Chopra P et al (2012) Age-associated DNA methylation in pediatric populations. Genome Res 22:623\u2013632. https:\/\/doi.org\/10.1101\/gr.125187.111","journal-title":"Genome Res"},{"key":"2826_CR10","doi-asserted-by":"publisher","first-page":"28657","DOI":"10.1038\/srep28657","volume":"6","author":"K Almstrup","year":"2016","unstructured":"Almstrup K, Lindhardt Johansen M, Busch AS et al (2016) Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. Sci Rep 6:28657. https:\/\/doi.org\/10.1038\/srep28657","journal-title":"Sci Rep"},{"key":"2826_CR11","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/15592294.2017.1414127","volume":"13","author":"AM Binder","year":"2018","unstructured":"Binder AM, Corvalan C, Mericq V et al (2018) Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Epigenetics 13:85\u201394. https:\/\/doi.org\/10.1080\/15592294.2017.1414127","journal-title":"Epigenetics"},{"key":"2826_CR12","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s11914-019-00527-9","volume":"17","author":"P Muthuirulan","year":"2019","unstructured":"Muthuirulan P, Capellini TD (2019) Complex phenotypes: mechanisms underlying variation in human stature. Curr Osteoporos Rep 17:301\u2013323. https:\/\/doi.org\/10.1007\/s11914-019-00527-9","journal-title":"Curr Osteoporos Rep"},{"key":"2826_CR13","first-page":"43","volume":"92","author":"C Barstow","year":"2015","unstructured":"Barstow C, Rerucha C (2015) Evaluation of short and tall stature in children. Am Fam Physician 92:43\u201350","journal-title":"Am Fam Physician"},{"key":"2826_CR14","doi-asserted-by":"publisher","unstructured":"AW Root 2020 Genetic Regulation of adult stature in humans J ClinEndocrinol Metab 105.\u00a0https:\/\/doi.org\/10.1210\/clinem\/dgaa210","DOI":"10.1210\/clinem\/dgaa210"},{"key":"2826_CR15","doi-asserted-by":"publisher","first-page":"3641","DOI":"10.1093\/hmg\/ddy271","volume":"27","author":"L Yengo","year":"2018","unstructured":"Yengo L, Sidorenko J, Kemper KE et al (2018) Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum Mol Genet 27:3641\u20133649. https:\/\/doi.org\/10.1093\/hmg\/ddy271","journal-title":"Hum Mol Genet"},{"key":"2826_CR16","doi-asserted-by":"publisher","unstructured":"M Guo Z Liu J Willen et al 2017 Epigenetic profiling of growth plate chondrocytes sheds insight into regulatory genetic variation influencing height Elife 6.\u00a0https:\/\/doi.org\/10.7554\/eLife.29329","DOI":"10.7554\/eLife.29329"},{"key":"2826_CR17","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.ecl.2017.01.001","volume":"46","author":"YH Jee","year":"2017","unstructured":"Jee YH, Andrade AC, Baron J, Nilsson O (2017) Genetics of short stature. Endocrinol Metab Clin North Am 46:259\u2013281. https:\/\/doi.org\/10.1016\/j.ecl.2017.01.001","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2826_CR18","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1111\/cen.12867","volume":"84","author":"M Ouni","year":"2016","unstructured":"Ouni M, Castell AL, Rothenbuhler A, Linglart A, Bougneres P (2016) Higher methylation of the IGF1 P2 promoter is associated with idiopathic short stature. Clin Endocrinol (Oxf) 84:216\u2013221. https:\/\/doi.org\/10.1111\/cen.12867","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2826_CR19","doi-asserted-by":"publisher","unstructured":"S Peeters K Declerck M Thomas et al 2020 DNA methylation profiling and genomic analysis in 20 children with short stature who were born small for gestational age J ClinEndocrinol Metab 105.\u00a0https:\/\/doi.org\/10.1210\/clinem\/dgaa465","DOI":"10.1210\/clinem\/dgaa465"},{"key":"2826_CR20","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.ajhg.2017.12.008","volume":"102","author":"E Aref-Eshghi","year":"2018","unstructured":"Aref-Eshghi E, Rodenhiser DI, Schenkel LC et al (2018) Genomic DNA methylation signatures enable concurrent diagnosis and clinical genetic variant classification in neurodevelopmental syndromes. Am J Human Gene 102:156\u2013174. https:\/\/doi.org\/10.1016\/j.ajhg.2017.12.008","journal-title":"Am J Human Gene"},{"key":"2826_CR21","doi-asserted-by":"publisher","first-page":"563","DOI":"10.2217\/epi-2018-0192","volume":"11","author":"B Sadikovic","year":"2019","unstructured":"Sadikovic B, Aref-Eshghi E, Levy MA, Rodenhiser D (2019) DNA methylation signatures in mendelian developmental disorders as a diagnostic bridge between genotype and phenotype. Epigenomics 11:563\u2013575. https:\/\/doi.org\/10.2217\/epi-2018-0192","journal-title":"Epigenomics"},{"key":"2826_CR22","doi-asserted-by":"publisher","first-page":"38803","DOI":"10.1038\/srep38803","volume":"6","author":"RL Hood","year":"2016","unstructured":"Hood RL, Schenkel LC, Nikkel SM et al (2016) The defining DNA methylation signature of Floating-Harbor syndrome. Sci Rep 6:38803. https:\/\/doi.org\/10.1038\/srep38803","journal-title":"Sci Rep"},{"key":"2826_CR23","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.fsigen.2017.11.004","volume":"33","author":"J Naue","year":"2018","unstructured":"Naue J, Hoefsloot HCJ, Kloosterman AD, Verschure PJ (2018) Forensic DNA methylation profiling from minimal traces: how low can we go? Forensic Sci Int Genet 33:17\u201323. https:\/\/doi.org\/10.1016\/j.fsigen.2017.11.004","journal-title":"Forensic Sci Int Genet"},{"key":"2826_CR24","doi-asserted-by":"publisher","DOI":"10.1007\/s00414-021-02736-3","author":"J Becker","year":"2021","unstructured":"Becker J, B\u00f6hme P, Reckert A et al (2021) Evidence for differences in DNA methylation between Germans and Japanese. Int J Legal Med. https:\/\/doi.org\/10.1007\/s00414-021-02736-3","journal-title":"Int J Legal Med"},{"key":"2826_CR25","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.fsigen.2017.07.015","volume":"31","author":"J Naue","year":"2017","unstructured":"Naue J, Hoefsloot HCJ, Mook ORF et al (2017) Chronological age prediction based on DNA methylation: massive parallel sequencing and random forest regression. Forensic Sci Int Genet 31:19\u201328. https:\/\/doi.org\/10.1016\/j.fsigen.2017.07.015","journal-title":"Forensic Sci Int Genet"},{"key":"2826_CR26","doi-asserted-by":"publisher","first-page":"R24","DOI":"10.1186\/gb-2014-15-2-r24","volume":"15","author":"CI Weidner","year":"2014","unstructured":"Weidner CI, Lin Q, Koch CM et al (2014) Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol 15:R24. https:\/\/doi.org\/10.1186\/gb-2014-15-2-r24","journal-title":"Genome Biol"},{"key":"2826_CR27","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1080\/15592294.2015.1080413","volume":"10","author":"B Bekaert","year":"2015","unstructured":"Bekaert B, Kamalandua A, Zapico SC, Van de Voorde W, Decorte R (2015) Improved age determination of blood and teeth samples using a selected set of DNA methylation markers. Epigenetics 10:922\u2013930. https:\/\/doi.org\/10.1080\/15592294.2015.1080413","journal-title":"Epigenetics"},{"key":"2826_CR28","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1161\/CIRCRESAHA.119.315397","volume":"125","author":"D Sun","year":"2019","unstructured":"Sun D, Zhang T, Su S et al (2019) Body Mass Index Drives Changes in DNA Methylation: A Longitudinal Study. Circ Res 125:824\u2013833. https:\/\/doi.org\/10.1161\/CIRCRESAHA.119.315397","journal-title":"Circ Res"},{"key":"2826_CR29","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.jgg.2021.02.008","volume":"48","author":"X Fan","year":"2021","unstructured":"Fan X, Zhao S, Yu C et al (2021) Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. J Genet Genomics 48:396\u2013402. https:\/\/doi.org\/10.1016\/j.jgg.2021.02.008","journal-title":"J Genet Genomics"},{"key":"2826_CR30","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1210\/er.2013-1053","volume":"35","author":"MF Azevedo","year":"2014","unstructured":"Azevedo MF, Faucz FR, Bimpaki E et al (2014) Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev 35:195\u2013233. https:\/\/doi.org\/10.1210\/er.2013-1053","journal-title":"Endocr Rev"},{"key":"2826_CR31","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.plipres.2006.01.004","volume":"45","author":"A Jakobsson","year":"2006","unstructured":"Jakobsson A, Westerberg R, Jacobsson A (2006) Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res 45:237\u2013249. https:\/\/doi.org\/10.1016\/j.plipres.2006.01.004","journal-title":"Prog Lipid Res"},{"key":"2826_CR32","doi-asserted-by":"publisher","unstructured":"Dueva R, Iliakis G (2020) Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond. NAR Cancer 2: zcaa022. https:\/\/doi.org\/10.1093\/narcan\/zcaa022","DOI":"10.1093\/narcan\/zcaa022"},{"key":"2826_CR33","doi-asserted-by":"publisher","unstructured":"E Keller W Kiess R Pf\u00e4ffle A Keller 2007 Kleinwuchs Kinder- und Jugendmedizin 7 209 216.\u00a0https:\/\/doi.org\/10.1055\/s-0038-1625650","DOI":"10.1055\/s-0038-1625650"}],"container-title":["International Journal of Legal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00414-022-02826-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00414-022-02826-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00414-022-02826-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T17:03:35Z","timestamp":1654535015000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00414-022-02826-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":33,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["2826"],"URL":"https:\/\/doi.org\/10.1007\/s00414-022-02826-w","relation":{},"ISSN":["0937-9827","1437-1596"],"issn-type":[{"value":"0937-9827","type":"print"},{"value":"1437-1596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,12]]},"assertion":[{"value":"29 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human tissue were in concordance with the ethical standards of the institutional and\/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards (approved by Ethics Committee at the Medical Faculty of Heinrich-Heine University: HEBE-project, study number 5049). This article does not contain any studies with animals performed by any of the authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study and\/ or from legal guardians.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"W.W. is cofounder of Cygenia GmbH () that may provide service for analysis of epigenetic age. Apart from this, the authors have no conflict of interest to declare that are relevant to the content of this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}