Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

Abstract

Haploinsufficiency of the gene encoding the insulin-like growth factor 1 receptor (IGF1R), either caused by telomeric 15q26 deletions, or by heterozygous point mutations in IGF1R, segregate with short stature and various other phenotypes, including microcephaly and dysmorphic facial features. Psychomotor retardation and behavioral anomalies have been seen in some cases. Here we report small, intragenic deletions of IGF1R, identified by chromosome microarray analysis in two unrelated families affected primarily with neuropsychiatric phenotypes including developmental delay, intellectual disability and aggressive/autoaggressive behaviors. The deletions are in frame, and both wild-type and mutant mRNAs are expressed as measured by quantitative real-time PCR. While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.

Figure 1

Intragenic deletions in IGF1R identified by exon-targeted aCGH. (a, b) Microarray plots of index patient I-1 (a) and II-1 (b). Deleted exons represented as red boxes. (c) Schematic representation of intragenic deletions of IGF1R in probands I-1 and II-1 affecting exons 3 and 3–5, respectively. Minimal intervals displayed (2 kb and 40 kb). Plotting is based on UCSC Genome Build hg19 and the minimum interval detected to be deleted by aCGH.

Figure 2

Quantitative real-time PCR analysis of IGF1R mRNA in peripheral blood. ‘2/3' Indicates the abundance of wild-type IGF1R mRNA, amplified by using primers flanking the exon 2/exon 3 boundary. ‘10/11' Indicates the abundance of total (wild-type and mutant) IGF1R mRNA, using primers flanking the exon 10/exon 11 boundary. The abundance of mutant IGF1R mRNA can be deduced by subtracting the wild-type (2/3) expression from the total (10/11) expression. Note the inter- and intra-familial variability of IGF1R mRNA expression. All expression levels are normalized to GAPDH and to a normal, age-matched control. All reactions were carried out in triplicate; error bars indicate SD.