{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:13:31Z","timestamp":1787022811323,"version":"build-2736575974"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"6","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,12]]},"abstract":"\n Background<\/jats:title>\n GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal\/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal\/high IGF-1 levels. The prevalence of genetic defects is unknown.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A genetic diagnosis was discovered 38\/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19\/IGF2 region or mUPD7 consistent with Silver\u2013Russell Syndrome (total with genetic diagnosis 51\/107, 48% or 41\/97, 42% probands). WES also identified homozygous putative variants in\n FANCA<\/jats:italic>\n and\n PHKB<\/jats:italic>\n in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Comprehensive genetic testing confirms the genetic heterogeneity of GH\/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.<\/jats:p>\n <\/jats:sec>","DOI":"10.1530\/eje-17-0453","type":"journal-article","created":{"date-parts":[[2017,9,4]],"date-time":"2017-09-04T20:25:33Z","timestamp":1504556733000},"page":"485-501","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":32,"title":["Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity"],"prefix":"10.1093","volume":"177","author":[{"given":"Lucy","family":"Shapiro","sequence":"first","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumana","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina G","family":"Ramadan","sequence":"additional","affiliation":[{"name":"2Department of Pediatrics and Endocrinology Unit, Sabah Hospital, Safat, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M","family":"Davies","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin O","family":"Savage","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise A","family":"Metherell","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L","family":"Storr","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref11","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1073\/pnas.86.20.8083","article-title":"Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type 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