Increasing knowledge in IGF1R defects: lessons from 35 new patients

Abstract

BackgroundThe 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.MethodsDNA 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.ResultsWe 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.ConclusionWe 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.

Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study

“…Aside from genes associated with SRS, CDKN1C and IGF2, [7][8][9][10] variants affected IGF1R, ORC1 (associated with Meier-Gorlin syndrome) and LZTR1 (associated with Noonan syndrome). [35][36][37] These findings parallel those recently obtained through exome and gene panel approaches. [ 13 14] Further potentially-pathogenic variants were identified but detailed clinical follow-up was beyond the scope of this project.…”

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

“…In all these patients, severe postnatal (and intrauterine) growth retardation was reported, and this feature was the reason for inclusion in the study. However, microcephaly is the clinical feature which allows the discrimination between SRS and the majority of its differential diagnosis, in our cohort IGF1R disturbances and MGS1 [19,20]. Nevertheless, it should be noted that the patient with the OBSL1 variant exhibited relative macrocephaly at least at the age of 2 years 5 months, and our case confirms that 3-M syndrome is a relevant differential diagnosis of SRS [21].…”

Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients

“…This may be because of phenotypic variability in the patients with IGF1R abnormality [28]. To our knowledge, four patients with pathogenic or likely pathogenic heterozygous variants in IGF1R were reported to have inherited them from parents with normal stature [28,35]. Second, patient 7 with Floating-Harbor syndrome suffered from Perthes disease.…”