IGF1R Variants in Patients With Growth Impairment: Four Novel Variants and Genotype-Phenotype Correlations

Objective: IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, as well as microcephaly. Both autosomal-dominant and autosomal-recessive inheritance patterns have been reported. This study aimed to analyze the IGF1R gene in children with growth impairment using whole-exome sequencing (WES) and assess the clinical features with the autosomal-dominant and autosomal-recessive models. Methods: We performed WES in 28 unrelated patients and found three children harboring IGF1R gene variants. We compared the clinical findings in our cases carrying IGF1R mutations to those in patients reported in the Human Gene Mutation Database (HGMD). Results: We identified four IGF1R gene variations by WES in three unrelated patients, including one missense variant [c.3740T>C (p.M1247T)] (patient 1) inherited from an affected mother, one missense variant [c.744T>G (p.C248W)] (patient 2) inherited from an affected father, and two compound heterozygous variations [c.2305G>C (p.E769Q) and c. 2684G>A (p.R895Q)] (patient 3). To date, 22 patients have been described as harboring pathogenic variations in IGF1R in the HGMD. We found that patients with compound heterozygous or homozygous variations displayed more severe phenotypes that were mainly characterized by developmental and speech delays, as well as mental retardation. Conclusion: We identified four pathogenic variations in the IGF1R gene, which expanded the known mutation spectrum. Through a comparison among patients with reported IGF1R pathogenic variations, this study determined that an autosomal-recessive inheritance model of the IGF1R gene may result in a more severe phenotype with developmental and speech delays, as well as mental retardation.