TY - JOUR T1 - Increasing knowledge in <em>IGF1R</em> defects: lessons from 35 new patients JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2019-106328 SP - jmedgenet-2019-106328 AU - Eloïse Giabicani AU - Marjolaine Willems AU - Virginie Steunou AU - Sandra Chantot-Bastaraud AU - Nathalie Thibaud AU - Walid Abi Habib AU - Salah Azzi AU - Bich Lam AU - Laurence Bérard AU - Hélène Bony-Trifunovic AU - Cécile Brachet AU - Elise Brischoux-Boucher AU - Emmanuelle Caldagues AU - Regis Coutant AU - Marie-Laure Cuvelier AU - Georges Gelwane AU - Isabelle Guemas AU - Muriel Houang AU - Bertrand Isidor AU - Claire Jeandel AU - James Lespinasse AU - Catherine Naud-Saudreau AU - Monique Jesuran-Perelroizen AU - Laurence Perrin AU - Juliette Piard AU - Claire Sechter AU - Pierre-François Souchon AU - Caroline Storey AU - Domitille Thomas AU - Yves Le Bouc AU - Sylvie Rossignol AU - Irène Netchine AU - Frédéric Brioude Y1 - 2019/10/05 UR - http://jmg.bmj.com/content/early/2019/10/05/jmedgenet-2019-106328.abstract N2 - 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. ER -