{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:14:40Z","timestamp":1775978080069,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.15016.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T00:00:00Z","timestamp":1587427200000}}],"reference-count":35,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T00:00:00Z","timestamp":1587427200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["IS-BRC-1215-20012"],"award-info":[{"award-number":["IS-BRC-1215-20012"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["209328\/Z\/17\/Z"],"award-info":[{"award-number":["209328\/Z\/17\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000325","name":"Wellbeing of Women","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000325","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001279","name":"Great Ormond Street Hospital Children's Charity","doi-asserted-by":"crossref","award":["V2518"],"award-info":[{"award-number":["V2518"]}],"id":[{"id":"10.13039\/501100001279","id-type":"DOI","asserted-by":"crossref"}]},{"name":"GOSH Biomedical Research Centre","award":["IS-BRC-1215-20012"],"award-info":[{"award-number":["IS-BRC-1215-20012"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"\n Background:<\/ns3:bold>\n Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted\/maternally expressed gene in humans. Loss-of-function variants in\n CDKN1C<\/ns3:italic>\n are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas \u201cgain-of-function\u201d variants in\n CDKN1C<\/ns3:italic>\n that increase protein stability cause growth restriction as part of IMAGe syndrome (\n I<\/ns3:underline>\n ntrauterine growth restriction,\n M<\/ns3:underline>\n etaphyseal dysplasia,\n A<\/ns3:underline>\n drenal hypoplasia and\n Ge<\/ns3:underline>\n nital anomalies). As three families have been reported with\n CDKN1C<\/ns3:italic>\n mutations who have fetal growth restriction (FGR)\/Silver-Russell syndrome (SRS)\n without<\/ns3:italic>\n adrenal insufficiency, we investigated whether pathogenic variants in\n CDKN1C<\/ns3:italic>\n could be associated with isolated growth restriction or recurrent loss of pregnancy.\n <\/ns3:p>\n \n Methods:<\/ns3:bold>\n Analysis of published literature was undertaken to review the localisation of variants in\n CDKN1C<\/ns3:italic>\n associated with IMAGe syndrome or fetal growth restriction.\n CDKN1C<\/ns3:italic>\n expression in different tissues was analysed in available RNA-Seq data (Human Protein Atlas). Targeted sequencing was used to investigate the critical region of\n CDKN1C<\/ns3:italic>\n for potential pathogenic variants in SRS (n=66), FGR (n=37), DNA from spontaneous loss of pregnancy (n= 22) and women with recurrent miscarriages (n=78) (total n=203).\n <\/ns3:p>\n \n Results:<\/ns3:bold>\n All published single nucleotide variants associated with IMAGe syndrome are located in a highly-conserved \u201chot-spot\u201d within the PCNA-binding domain of CDKN1C between codons 272-279. Variants associated with familial growth restriction but normal adrenal function currently affect codons 279 and 281.\n CDKN1C<\/ns3:italic>\n is highly expressed in the placenta compared to adult tissues, which may contribute to the FGR phenotype and supports a role in pregnancy maintenance. In the patient cohorts studied no pathogenic variants were identified in the PCNA-binding domain of CDKN1C.\n <\/ns3:p>\n \n Conclusion:<\/ns3:bold>\n CDKN1C is a key negative regulator of growth. Variants in a very localised \u201chot-spot\u201d cause growth restriction, with or without adrenal insufficiency. However, pathogenic variants in this region are not a common cause of isolated fetal growth restriction phenotypes or loss-of-pregnancy\/recurrent miscarriages.\n <\/ns3:p>","DOI":"10.12688\/f1000research.15016.2","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T08:05:08Z","timestamp":1587456308000},"page":"90","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Analysis of CDKN1C in fetal growth restriction and pregnancy loss"],"prefix":"10.12688","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8897-7697","authenticated-orcid":false,"given":"Jenifer P.","family":"Suntharalingham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miho","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8274-7241","authenticated-orcid":false,"given":"Federica","family":"Buonocore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"del Valle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nita","family":"Solanky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charalambos","family":"Demetriou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Regan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gudrun E.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Achermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2020,4,21]]},"reference":[{"key":"ref-1","article-title":"Analysis of CDKN1C in fetal growth restriction and pregnancy loss.","author":"J Achermann","year":"2018","journal-title":"Open 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The potential role of CDKN1C in pregnancy maintenance and its putative involvement in pregnancy loss is interesting, and an aspect that in future could be better investigated by extending the number of the cases to analyze. <\/i>Response: In the revised submission, we have used the Agilent HaloPlex panel, as well as a Nonacus 3T cell target enrichment approach to add data from an additional 27 subjects (POC (n= 1); women with history of recurrent miscarriage (n=7); Silver Russell Syndrome (n=8) and fetal growth restriction (n=11) ). We have modified Table 1, Supplementary data and Figures, and relevant places in the text, accordingly, and included a Supplementary Data 8 for Nonacus coverage. A reference for the Nonacus methods in included (Buonocore et al., 2019). \nIt would be interesting if the authors could report the analysis of the variants extended to the CDKN1C domains other than the region corresponding to the \u201chot spot\u201d PCNA-binding domain (at least for cases analysed by NGS). <\/i>Response: Although our focus was on the PCNA-binding domain, we agree it is valid to look at regions outside of the hotspot and thank the reviewer (and reviewer 2) for the suggestion.Analysis of CDKN1C using the gnomAD browser (accessed March 2020) shows an expected number of synonymous changes (o\/e =1.06 (0.86-1.31)) but fewer missense (o\/e= 0.51 (0.42-0.63)) and pLoF changes (o\/e=0 (0-0.53)) than expected. (https:\/\/gnomad.broadinstitute.org\/gene\/ENSG00000129757?dataset=gnomad_r2_1)Based on the fact that random variants within a gene are more likely to cause disruption rather than gain-of-function, the low number of observed missense changes is more likely to represent an intolerance to disruption and loss of function associated with overgrowth and Beckwith-Wiedemann Syndrome, rather than rare gain of function changes associated with FGR\/IMAGe syndrome.  We have undertaken an extended analysis of data for the gene. We did not detect any category 1 variants (nonsense, frameshift, canonical splice site variants) at all, which is not surprising, as these would be loss of function and predicted to be associated with overgrowth.We only identified two category 2 (non-synonymous missense) variants in the cohort, both in women who have had recurrent miscarriages.  One of these is a 9:g.2906703A>G variant (rs201715947) predicted to result in a p.Leu6Pro change that is present in gnomAD with allelic frequency of 0.0001102 (8\/72604).  The other variant is a 9:g.2906589C>T predicted to result in a p. Arg44His. This variant is not present in gnomAD but a p.Arg44Leu is present in one male. Although the SIFT score for this variant suggests it is deleterious, we find that prediction models are not always reliable for gain-of-function effects. On balance, we do not feel that either of these variants are likely to be clinically pathogenic although we cannot say this definitively.  We have commented on this in the revised results. More certain is our finding that there is not a large pool of additional CDKN1C variants in our cohort outside of the PCNA binding domain.\nMinor comments:\u2022  The authors should clarify why they have analyzed CDKN1C variants only in the isolated SRS cases, excluding the familial cases.<\/i>Response: Our cohort was only made up of sporadic Silver Russell Syndrome subjects; we had no familial cases. We have mentioned this in the methods. \n\u2022  Most of information reported in Table 2 are already present in Figure 1, therefore Table 2 could be removed or reported as Supplementary Table 2.<\/i>Response: We agree there is some overlap, but we would prefer to keep both in the main body of text as Figure 1 shows the structure of CDKN1C and position of variants, and Table 2 shows nucleotide data, whether mineralocorticoid or glucocorticoid was given, and links to the original references.","URL":"https:\/\/f1000research.com\/articles\/8-90\/v2#referee-comment-5410","order":1,"name":"referee-comment-5410","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.25093.r62553, Amanda J. Drake, Kahyee Hor, University\/British Heart Foundation Centre for Cardiovascular Science, The Queen\u2019s Medical Research Institute, University of Edinburgh, Edinburgh, UK, 22 Apr 2020, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/8-90\/v2#referee-response-62553","order":2,"name":"referee-response-62553","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 209328\/Z\/17\/Z) with research support from Great Ormond Street Hospital Children's Charity (grant V2518) and the NIHR GOSH BRC (IS-BRC-1215-20012). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The Baby Bio Bank was funded by Wellbeing of Women. M.I. and C.D. are funded by the UK MRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}