Increasing knowledge in IGF1R defects: lessons from 35 new patients. Issue 3 (5th October 2019)

• Record Type: Journal Article
• Authors: Giabicani, Eloïse; Willems, Marjolaine; Steunou, Virginie; Chantot-Bastaraud, Sandra; Thibaud, Nathalie; Abi Habib, Walid; Azzi, Salah; Lam, Bich; Bérard, Laurence; Bony-Trifunovic, Hélène; Brachet, Cécile; Brischoux-Boucher, Elise; Caldagues, Emmanuelle; Coutant, Regis; Cuvelier, Marie-Laure; Gelwane, Georges; Guemas, Isabelle; Houang, Muriel; Isidor, Bertrand; Jeandel, Claire; Lespinasse, James; Naud-Saudreau, Catherine; Jesuran-Perelroizen, Monique; Perrin, Laurence; Piard, Juliette; Sechter, Claire; Souchon, Pierre-François; Storey, Caroline; Thomas, Domitille; Le Bouc, Yves; Rossignol, Sylvie; Netchine, Irène; Brioude, Frédéric;
• Is Part Of: Journal of medical genetics. Volume 57:Issue 3(2020)
• Page Start: 160
• Page End: 168
• Publication Date: 2019-10-05
• Subjects: IGF1R -- IGF-I -- fetal growth restriction -- homozygous variant -- small for gestational age; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2019-106328
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. Methods: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. Results: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R . Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. Conclusion: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.