Increasing knowledge in IGF1R defects: lessons from 35 new patients.

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• The type 1 insulin-like growth factor receptor (IGF1R) is essential for fetal growth, mediating IGF-I and IGF-II effects.
• A clinical score for diagnosing IGF1R defects was recently established but lacked external validation.
• Variants of unknown significance (VUS) in IGF1R require robust classification methods.

Purpose of the Study:

• To externally validate a clinical diagnostic score for IGF1R defects in a large patient cohort.
• To develop and implement an in vitro functional assay for classifying IGF1R variants, particularly VUS.

Main Methods:

• Genetic analysis of DNA for deletions and single nucleotide variants (SNVs) in 35 patients.
• Western blot analysis of fibroblast cultures to assess downstream AKT phosphorylation after IGF-I stimulation.
• Evaluation of a previously proposed clinical score for diagnostic accuracy.

Main Results:

• Twenty-one IGF1R defects were identified in 35 patients, including deletions and various SNVs.
• Key clinical features included being small for gestational age, short stature, and microcephaly.
• Functional studies revealed decreased AKT phosphorylation in patients with tested SNVs.

Conclusions:

• The clinical score demonstrated high accuracy (95.2% sensitivity) for diagnosing IGF1R defects.
• Eight new pathogenic IGF1R variants were identified, including a novel homozygous SNV.
• An efficient functional test was developed, proving valuable for assessing SNV pathogenicity, especially for VUS.