Increasing knowledge in defects: lessons from 35 new patients.

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 defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified 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 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 . Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.

Conclusion: We report eight new pathogenic variants of and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of 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.