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.
- fetal growth restriction
- homozygous variant
- small for gestational age
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Contributors EG: wrote the manuscript, performed the experiments, collected and analysed the data and revised the manuscript. MW: collected and analysed the data and revised the manuscript. VS: performed the experiments. SC-B, SA, BL: performed the experiments, analysed the data and helped in revising the manuscript. NT: performed the experiments. WAH: analysed the data and helped in revising the manuscript. LB, HB-T, CB, EB-B, EC, RC, M-LC, GG, IG, MH, BI, CJ, JL, CN-S, MJ-P, LPS, JP, P-FS, CS, YLB and SR: collected data and helped to revise the manuscript. DT: performed the experiments, collected data and helped to revise the manuscript. IN: analysed the data and revised the manuscript. FB: analysed the data, wrote and revised the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.
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