{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:13:16Z","timestamp":1788318796890,"version":"build-2803163510"},"reference-count":23,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pathogenic variants on the paternal allele of\n                    <jats:italic>IGF2<\/jats:italic>\n                    are linked to Silver\u2013Russell syndrome (SRS). This report describes two unrelated individuals\u2014a 5\u2010year\u2010old girl and an adult female\u2014with de novo IGF2 missense variants, both diagnosed with SRS. While one exhibited normal development, the other had intellectual disability, highlighting phenotypic variability. A review of 20 individuals with IGF2 variants revealed that SRS features, as defined by the Netchine\u2010Harbison Clinical Scoring System, were most common. Additional recurrent traits included delayed speech and motor development, under\u2010masculinized male genitalia, hand\/foot anomalies, and congenital heart defects. Growth faltering patterns varied, and intellectual disability was seen in some. We also demonstrated that long\u2010read sequencing can determine the allelic origin of de novo IGF2 variants using differentially methylated regions, eliminating the need for parental samples. This approach confirms long\u2010read sequencing as a powerful tool for identifying de novo variant origins in imprinted genes like\n                    <jats:italic>IGF2<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/cge.70239","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:21:18Z","timestamp":1788315678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Variants in the Imprinted\n                    <scp>\n                      <i>IGF2<\/i>\n                    <\/scp>\n                    Gene: A Review and Phasing of De Novo Variants Using Long\u2010Read Sequencing"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9421-3004","authenticated-orcid":false,"given":"Trine Maxel","family":"Juul","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-2080","authenticated-orcid":false,"given":"Susanne Eriksen","family":"Boonen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja Venborg","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Sygehus Lilleb\u00e6lt, Vejle Hospital  Vejle Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5852-5242","authenticated-orcid":false,"given":"Caroline Hey","family":"B\u00e6kgaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-8771","authenticated-orcid":false,"given":"Martin","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kib\u00e6k","sequence":"additional","affiliation":[{"name":"H. C. Andersen Children's Hospital Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Illum","sequence":"additional","affiliation":[{"name":"H. C. Andersen Children's Hospital Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malene","family":"Heideman","sequence":"additional","affiliation":[{"name":"H. C. Andersen Children's Hospital Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Hospital of Southern Jutland, Aabenraa Hospital  Aabenraa Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8343-3084","authenticated-orcid":false,"given":"Emilie Boye","family":"Lester","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5206-4327","authenticated-orcid":false,"given":"Christina","family":"Fagerberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Genetics Sygehus Lilleb\u00e6lt, Vejle Hospital  Vejle Denmark"},{"name":"Department of Regional Health Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"6","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1159\/000527123","article-title":"The History of the Insulin\u2010Like Growth Factor System","volume":"95","author":"Miller B. S.","year":"2022","journal-title":"Hormone Research in P\u00e6diatrics"},{"issue":"11","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1101\/gr.161800","article-title":"Sequence and Comparative Analysis of the Mouse 1\u2010Megabase Region Orthologous to the Human 11p15 Imprinted Domain","volume":"10","author":"Onyango P.","year":"2000","journal-title":"Genome Research"},{"issue":"8","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/ng1402","article-title":"Interaction Between Differentially Methylated Regions Partitions the Imprinted Genes Igf2 and H19 Into Parent\u2010Specific Chromatin Loops","volume":"36","author":"Murrell A.","year":"2004","journal-title":"Nature Genetics"},{"issue":"6","key":"e_1_2_9_5_1","first-page":"1655","article-title":"Human IGF2 Gene Epigenetic and Transcriptional Regulation: At the Core of Developmental Growth and Tumorigenic Behavior","volume":"11","author":"Scalia P.","year":"2023","journal-title":"Biomedicine"},{"issue":"12","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.3390\/cells11121886","article-title":"IGF2: Development, Genetic and Epigenetic Abnormalities","volume":"11","author":"S\u00e9l\u00e9nou C.","year":"2022","journal-title":"Cells"},{"issue":"1","key":"e_1_2_9_7_1","first-page":"dgz034","article-title":"IGF2 Mutations","volume":"105","author":"Masunaga Y.","year":"2020","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"issue":"4","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1056\/NEJMoa1415227","article-title":"Paternally Inherited IGF2 Mutation and Growth Restriction","volume":"373","author":"Begemann M.","year":"2015","journal-title":"New England Journal of Medicine"},{"issue":"2","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/gim.2017.105","article-title":"Genetic Disruption of the Oncogenic HMGA2\u2010PLAG1\u2010IGF2 Pathway Causes Fetal Growth Restriction","volume":"20","author":"Abi Habib W.","year":"2018","journal-title":"Genetics in Medicine"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41525-020-00140-1","article-title":"Partially Automated Whole\u2010Genome Sequencing Reanalysis of Previously Undiagnosed Pediatric Patients Can Efficiently Yield New Diagnoses","volume":"5","author":"James K. N.","year":"2020","journal-title":"NPJ Genomic Medicine"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3389\/fgene.2017.00105","article-title":"De Novo Mutation of Paternal IGF2 Gene Causing Silver\u2010Russell Syndrome in a Sporadic Patient","volume":"8","author":"Liu D.","year":"2017","journal-title":"Frontiers in Genetics"},{"issue":"12","key":"e_1_2_9_12_1","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 C.","year":"2018","journal-title":"American Journal of Medical Genetics. Part A"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.3389\/fgene.2019.01161","article-title":"Rare De Novo IGF2 Variant on the Paternal Allele in a Patient With Silver\u2010Russell Syndrome","volume":"10","author":"Xia C. L.","year":"2019","journal-title":"Frontiers in Genetics"},{"issue":"5","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/humu.24347","article-title":"Genome Sequencing Demonstrates High Diagnostic Yield in Children With Undiagnosed Global Developmental Delay\/Intellectual Disability: A Prospective Study","volume":"43","author":"Sun Y.","year":"2022","journal-title":"Human Mutation"},{"issue":"8","key":"e_1_2_9_15_1","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\u2010Russell Syndrome and Ectrodactyly","volume":"38","author":"Yamoto K.","year":"2017","journal-title":"Human Mutation"},{"issue":"11","key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"4373","DOI":"10.1210\/jc.2008-0819","article-title":"Severe Intrauterine Growth Retardation and Atypical Diabetes Associated With a Translocation Breakpoint Disrupting Regulation of the Insulin\u2010Like Growth Factor 2 Gene","volume":"93","author":"Murphy R.","year":"2008","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2022.969881","article-title":"Case Report: A Novel De Novo IGF2 Missense Variant in a Finnish Patient With Silver\u2010Russell Syndrome","volume":"10","author":"Loid P.","year":"2022","journal-title":"Frontiers in Pediatrics"},{"issue":"2","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrendo.2016.138","article-title":"Diagnosis and Management of Silver\u2010Russell Syndrome: First International Consensus Statement","volume":"13","author":"Wakeling E. L.","year":"2017","journal-title":"Nature Reviews. Endocrinology"},{"issue":"7","key":"e_1_2_9_19_1","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\u2010Genotypical Correlations in Silver\u2010Russell Syndrome","volume":"52","author":"Azzi S.","year":"2015","journal-title":"Journal of Medical Genetics"},{"issue":"8","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1210\/jc.2007-0354","article-title":"11p15 Imprinting Center Region 1 Loss of Methylation Is a Common and Specific Cause of Typical Russell\u2010Silver Syndrome: Clinical Scoring System and Epigenetic\u2010Phenotypic Correlations","volume":"92","author":"Netchine I.","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"issue":"7","key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1136\/jmg-2025-111282","article-title":"Long\u2010Read Sequencing Enables Trio\u2010Assisted Phasing of de Novo Variants in the Imprinted Gene MAGEL2","volume":"63","author":"Laver T. W.","year":"2026","journal-title":"Journal of Medical Genetics"},{"issue":"1","key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13073-025-01559-w","article-title":"A Comprehensive Long\u2010Read Sequencing System to Assess DNA Methylation at Differentially Methylated Regions and Imprinting\u2010Disorder\u2010Related Genes","volume":"17","author":"Urakawa T.","year":"2025","journal-title":"Genome Medicine"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.7554\/eLife.77898","article-title":"Genome\u2010Wide Detection of Imprinted Differentially Methylated Regions Using Nanopore Sequencing","volume":"11","author":"Akbari V.","year":"2022","journal-title":"eLife"},{"issue":"1","key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s13148-024-01775-y","article-title":"Methylation Changes and INS\u2010IGF2 Expression Predict Progression in Early\u2010Stage Wilms Tumor","volume":"16","author":"Jalal D.","year":"2024","journal-title":"Clinical Epigenetics"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70239","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70239","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70239","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:21:24Z","timestamp":1788315684000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70239"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":23,"alternative-id":["10.1111\/cge.70239"],"URL":"https:\/\/doi.org\/10.1111\/cge.70239","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cge.70239"}}