{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:22:50Z","timestamp":1790619770630,"version":"4.1.0"},"reference-count":33,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:p>Approximately 10% of children born small for gestational age (SGA) fail to achieve catch-up growth, resulting in persistent short stature and eligibility for growth hormone (GH) therapy under established guidelines. Pathogenic variants in insulin-like growth factor 1 receptor (IGF1R) are associated with SGA, syndromic short stature, neurocognitive impairment, and variable responsiveness to GH therapy. This study aimed to characterize the clinical phenotype and elucidate the molecular mechanism underlying a rare intronic variant in IGF1R identified in an affected family. Here, we performed whole-exome sequencing (WES) on a single individual, followed by segregation studies in the family and Sanger sequencing. cDNA studies were pursued to evaluate mis-spliced transcripts. WES of the proband\u2019s affected mother revealed a rare heterozygous variant in IGF1R (NM_000875.5): c.3722+5G&amp;gt;A. Sanger sequencing confirmed segregation of the variant with the affected status in available family members. cDNA analysis showed that the variant results in intronic retention of 134 nucleotides immediately following the penultimate exon of IGF1R. This leads to a frameshift and introduction of a premature truncation codon, supporting the classification of the variant as likely pathogenic. Our study highlights the utility of genetic testing in SGA children with persistent short stature. By characterizing a novel IGF1R intronic variant causing aberrant splicing, we expand the understanding of its clinical spectrum and molecular underpinning. The findings underscore the importance of molecular diagnostics in unexplained short stature and neurodevelopmental disorders and may inform future therapeutic strategies targeting the IGF1R signaling.<\/jats:p>","DOI":"10.1530\/jme-25-0002","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T15:36:38Z","timestamp":1759505798000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":1,"title":["Intronic\n                    <i>IGF1R<\/i>\n                    variant causing aberrant splicing, short stature, and neurological impairments"],"prefix":"10.1530","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-038X","authenticated-orcid":true,"given":"Liya","family":"Kerem","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Hadassah Medical Organization 1 , ,","place":["Jerusalem, Israel"]},{"name":"Faculty of Medicine, Hebrew University of Jerusalem 2 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Rips","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem 2 , ,","place":["Jerusalem, Israel"]},{"name":"Department of Genetics, Hadassah Medical Organization 3 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Zaretsky","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada the Hebrew University of Jerusalem 4 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itay","family":"Grundwag","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization 3 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehud","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada the Hebrew University of Jerusalem 4 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira","family":"Yanovsky-Dagan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization 3 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem 2 , ,","place":["Jerusalem, Israel"]},{"name":"Department of Genetics, Hadassah Medical Organization 3 , ,","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"2026070811351812900_bib1","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1056\/NEJMoa010107","article-title":"IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation","volume":"349","author":"Abuzzahab","year":"2003","journal-title":"N Engl J Med"},{"key":"2026070811351812900_bib2","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1007\/PL00000744","article-title":"Structure and function of the type 1 insulin-like growth factor receptor","volume":"57","author":"Adams","year":"2000","journal-title":"Cell Mol Life Sci"},{"key":"2026070811351812900_bib3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000504884","article-title":"Targeted searches of the electronic health record and genomics identify an etiology in three patients with short stature and high IGF-I levels","volume":"92","author":"Cabrera-Salcedo","year":"2019","journal-title":"Horm Res Paediatr"},{"key":"2026070811351812900_bib4","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1210\/jc.2006-2017","article-title":"Management of the child born small for gestational age through to adulthood: a consensus statement of the international societies of pediatric endocrinology and the growth hormone research society","volume":"92","author":"Clayton","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070811351812900_bib33","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s12920-019-0647-8","article-title":"Genome analysis and knowledge-driven variant interpretation with TGex","volume":"12","author":"Dahary","year":"2019","journal-title":"BMC Med Genomics"},{"key":"2026070811351812900_bib5","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/bies.201400190","article-title":"Insulin\/receptor binding: the last piece of the puzzle? 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