Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp)

Summary Background Insulin‐like growth factor 1 insensitivity caused by IGF1R mutations has been previously identified as one of the causes of growth impairment in children born small for gestational age (SGA). Objective To analyse the IGF1R in children born SGA. Subjects From an initial cohort of 54 sequential children born SGA, without catch‐up growth, 25 children were selected for this IGF1R study due to the presence of serum IGF‐1 values above the mean for their age and sex. Methods The proximal IGF1R promoter region, the entire coding region and the exon–intron boundaries were directly sequenced, and multiplex ligation‐dependent probe amplification analysis was performed. Fibroblast cultures were developed from one patient with a mutation for the in vitro characterization of IGF‐1 insensitivity. Results The copy number variation analysis did not identify deletions involving the IGF1R gene. We identified two children carrying heterozygous nucleotide substitutions in IGF1R: c.16G>A/p.Gly6Arg and c.1531C>T/p.Arg511Trp. The first variant (p.Gly6Arg) was identified in control subjects (0·3%) and in a relative with normal growth; thus, it was considered to be a rare benign allelic variation. The second variant (p.Arg511Trp) was not found in 306 alleles from control subjects, and it segregated with the growth impairment phenotype in the patient's family. Fibroblasts obtained from this patient had a significantly reduced proliferative response and AKT phosphorylation after IGF‐1 stimulation compared with control fibroblasts. Conclusion The identification of an inactivating IGF1R mutation in the present cohort should encourage further studies of larger series to establish the precise frequency of this molecular defect in children with growth impairment of a prenatal onset.