Hemizygosity at the insulin-like growth factor I receptor (IGF1R) locus and growth failure in the ring chromosome 15 syndrome

Abstract

The ring chromosome 15 syndrome is characterized by mild-to-severe growth failure. We evaluated the status of the insulin-like growth factor I receptor (IGF1R) gene, which had previously been assigned to band 15q26 in several patients with de novo ring 15 chromosomes, to investigate a possible correlation between disruption or loss of the IGF1R gene with the severe growth failure phenotype. The presence or absence of the IGF1R gene on the ring 15 chromosomes of five patients was ascertained by in situ hybridization and gene-dosage (Southern) blotting. The location of the breakpoints was determined by typing polymorphic markers from the distal end of the long arm of chromosome 15 in both the probands and their parents. Deletion mapping determined that all breakpoints were distal to D15S100 and that the IGF1R gene is located between D15S107 and D15S87. Three patients who had suffered severe growth failure in early childhood were hemizygous at the IGF1R locus, while one patient with borderline short stature had two copies of the IGF1R gene. The correlation between IGF1R gene dosage and growth retardation demonstrated here in our ring chromosome 15 patients suggests a possible role for heterozygous IGF1R gene mutations or deletions in other cases of unexplained growth failure.