{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:54:13Z","timestamp":1779292453975,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,5]],"date-time":"2020-12-05T00:00:00Z","timestamp":1607126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16-00073"],"award-info":[{"award-number":["PI16-00073"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Health of the Basque Government","award":["GV2017\/111040"],"award-info":[{"award-number":["GV2017\/111040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Silver\u2013Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (\u224850%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (\u224810%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver\u2013Russell syndrome.<\/jats:p>","DOI":"10.3390\/genes11121461","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T11:50:49Z","timestamp":1607428249000},"page":"1461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel Variant in PLAG1 in a Familial Case with Silver\u2013Russell Syndrome Suspicion"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4156-9159","authenticated-orcid":false,"given":"Yerai","family":"Vado","sequence":"first","affiliation":[{"name":"Rare Diseases Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, 01009 Araba, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad del Pa\u00eds Vasco\/Euskal Herriko Unibertsitatea (UPV\/EHU), Vitoria-Gasteiz, 01006 Araba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5442-7873","authenticated-orcid":false,"given":"Arrate","family":"Pereda","sequence":"additional","affiliation":[{"name":"Rare Diseases Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, 01009 Araba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Llano-Rivas","sequence":"additional","affiliation":[{"name":"Service of Genetics, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, 48903 Bizkaia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nerea","family":"Gorria-Redondo","sequence":"additional","affiliation":[{"name":"Service of Paediatric Neurology, Araba University Hospital, Vitoria-Gasteiz, 01009 Araba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7211-0135","authenticated-orcid":false,"given":"Ignacio","family":"D\u00edez","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2424-5294","authenticated-orcid":false,"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[{"name":"Rare Diseases Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, 01009 Araba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,5]]},"reference":[{"key":"ref_1","first-page":"1040","article-title":"A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples)","volume":"47","author":"Russell","year":"1954","journal-title":"Proc. R. Soc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1542\/peds.12.4.368","article-title":"Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins","volume":"12","author":"Silver","year":"1953","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrendo.2016.138","article-title":"Diagnosis and management of Silver-Russell syndrome: First international consensus statement","volume":"13","author":"Wakeling","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/ajmg.1320350220","article-title":"Three-generation dominant transmission of the Silver-Russell syndrome","volume":"35","author":"Duncan","year":"1990","journal-title":"Am. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1136\/jmedgenet-2014-102979","article-title":"A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome","volume":"52","author":"Azzi","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1750-1172-5-19","article-title":"Silver-Russell syndrome: Genetic basis and molecular genetic testing","volume":"5","author":"Eggermann","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1097\/MOP.0000000000000379","article-title":"New clinical and molecular insights into Silver-Russell syndrome","volume":"28","author":"Giabicani","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/humu.23382","article-title":"Structural and sequence variants in patients with Silver-Russell syndrome or similar features\u2014Curation of a disease database","volume":"39","author":"Netchine","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1136\/jmedgenet-2013-101691","article-title":"CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome","volume":"50","author":"Brioude","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E2117","DOI":"10.1210\/jc.2014-1949","article-title":"A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes","volume":"99","author":"Kerns","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","first-page":"1398250","article-title":"Familial Russell-Silver Syndrome like Phenotype in the PCNA Domain of the CDKN1C Gene, a Further Case","volume":"2019","author":"Sabir","year":"2019","journal-title":"Case Rep. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/gim.2017.105","article-title":"Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction","volume":"20","author":"Brioude","year":"2018","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1056\/NEJMoa1415227","article-title":"Paternally Inherited IGF2 Mutation and Growth Restriction","volume":"373","author":"Begemann","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3389\/fgene.2017.00105","article-title":"De Novo Mutation of Paternal IGF2 Gene Causing Silver-Russell Syndrome in a Sporadic Patient","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1210\/clinem\/dgz034","article-title":"IGF2 Mutations: Report of Five Cases, Review of the Literature, and Comparison with H19\/IGF2:IG-DMR Epimutations","volume":"105","author":"Masunaga","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1002\/ajmg.a.40502","article-title":"Silver Russel syndrome in an aboriginal patient from Australia","volume":"176","author":"Poulton","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"K1","DOI":"10.1530\/EJE-18-0601","article-title":"A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation","volume":"180","author":"Rockstroh","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/humu.23253","article-title":"De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly","volume":"38","author":"Yamoto","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/jhg.2015.29","article-title":"A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype","volume":"60","author":"Citro","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1210\/clinem\/dgaa273","article-title":"HMGA2 variants in Silver-Russell syndrome: Homozygous and heterozygous occurrence","volume":"105","author":"Meyer","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13148-020-00865-x","article-title":"Contribution of gene mutations to Silver-Russell syndrome phenotype: Multigene sequencing analysis in 92 etiology-unknown patients","volume":"12","author":"Inoue","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/ng0297-170","article-title":"Promoter swapping between the genes for a novel zinc finger protein and \u03b2-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations","volume":"15","author":"Kas","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.3892\/ijo.2012.1641","article-title":"Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity","volume":"41","author":"Akhtar","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1097\/MCD.0000000000000114","article-title":"Temple syndrome misdiagnosed as Silver-Russell syndrome","volume":"25","author":"Luk","year":"2016","journal-title":"Clin. Dysmorphol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1002\/ajmg.a.37827","article-title":"A patient with Temple syndrome satisfying the clinical diagnostic criteria of Silver-Russell syndrome","volume":"170","author":"Goto","year":"2016","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1007\/s00125-013-2832-1","article-title":"Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients","volume":"56","author":"Docherty","year":"2013","journal-title":"Diabetologia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/ng0295-110","article-title":"An imprinted gene(s) for diabetes?","volume":"9","author":"Temple","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"338","DOI":"10.4161\/epi.27387","article-title":"Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort","volume":"9","author":"Azzi","year":"2013","journal-title":"Epigenetics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/ng.3664","article-title":"The rules and impact of nonsense-mediated mRNA decay in human cancers","volume":"48","author":"Lindeboom","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0022-2836(03)00243-2","article-title":"Assessment by molecular dynamics simulations of the structural determinants of DNA-binding specificity for transcription factor Sp1","volume":"328","author":"Marco","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_32","first-page":"106","article-title":"PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II","volume":"60","author":"Voz","year":"2000","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"131","DOI":"10.2174\/1874210601206010131","article-title":"Orthodontic management of silver-russell syndrome. A case report","volume":"6","author":"Sluzker","year":"2012","journal-title":"Open Dent. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/j.1469-8749.2004.tb00495.x","article-title":"Cognitive development in Silver-Russell syndrome: A sibling-controlled study","volume":"46","author":"Noeker","year":"2004","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Burgevin, M., Lacroix, A., Brown, G., Mikaty, M., Coutinho, V., Netchine, I., and Odent, S. (2019). Intellectual functioning in Silver-Russell syndrome: First study in adults. Appl. Neuropsychol. Adult, 1\u201312.","DOI":"10.1080\/23279095.2019.1644643"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/12\/1461\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:41:57Z","timestamp":1760179317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/12\/1461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,5]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["genes11121461"],"URL":"https:\/\/doi.org\/10.3390\/genes11121461","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,5]]}}}