IMPE Abstracts

Background: IGF-1 receptor (IGF-1R) is widely expressed across many cell types in fetal and postnatal tissues. IGF-1R activation by IGF-1 and IGF-2 generates several responses including proliferation, and the protection of cells from apoptosis. Signaling through IGF-1R is the principal pathway responsible for somatic growth in fetal mammals, whereas in postnatal animals is achieved through synergistic interaction of growth hormone and the IGFs. IGF-1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation. Only four pathogenic intronic variants have been described to date.

Aim: To report and functionally characterize a novel intronic IGF1R gene variant.

Case report: A 46, XY patient was born pre-term (34 weeks) with appropriate weight (+0.6 SDS) and length (-1.3 SDS) for gestational age. He was under follow-up since 8,6 years old (y-o) by a pediatric endocrinologist for short stature, microcephaly and dysmorphic phenotype. External genitalia, serum GH levels (post Arginine +7.1 ng/ml) and IGF-1 (+1.23 SDS) were normal. His mother and sister had a history of intrauterine growth retardation, short stature and microcephaly. At 10 y-o he presented clinical and biochemical signs of hyperandrogenism without signs of pubertal development. He was diagnosed with congenital adrenal hyperplasia due 21-hydroxylase deficiency non-classical form, confirmed by molecular analysis.

Methods and results: IGF1R gene was sequenced from genomic DNA extracted from peripheral blood leukocytes. The variant (NM_000875.5): c.1462+4A>T was detected in intron 6 in heterozygous state, not previously described. It was classified as of uncertain significance (VUS) according to ACMG (PM2, PP3, PP1). In silico splicing analysis tools predicted the loss of splicing donor site. cDNA analysis, obtained from RNA extracted from peripheral blood leukocytes of the patient, confirmed the deletion of exon 6 and hence the appearance of a premature stop codon. His mother and sister, who share the same phenotype, were heterozygous while it was not found in his father.

Conclusion: We report a novel splicing site intronic variant c.1462+4A>T in IGF1R gene, in a boy under follow-up for short stature and microcephaly. Functional studies revealed an aberrant mRNA splicing, resulting in the loss of exon 6 generating the appearance of a premature stop codon. This mRNA variant would lead to a severely truncated protein that lacks entire β and part of α chain of IGF1R. This finding suggest that this mutation would affect the functionality of the IGF1R and causes the phenotype of this family.