Abstract
ObjectiveCopy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1).Design and methodsArray comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions.ResultsBoth cohorts were enriched for class 3–5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts.ConclusionsOur cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.
Highlights
The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis is essential for normal human growth
Copy number variation (CNV) were identified in a total of 10/63 (16%) subjects; 7/63 (11%) (6 growth hormone insensitivity (GHI), 1 IGF-1 insensitivity) had pathogenic or likely pathogenic CNVs and 3/63 (5%) (1 GHI and 2 IGF-1 insensitivity) variant of uncertain https://eje.bioscientifica.com https://eje.bioscientifica.com significance (VUS) CNVs (Fig. 1A and Table 1)
There were no significant differences between mean height, age, sex, birth weight (BW) standard deviation scores (SDS) or IGF-1 SDS in the subjects harbouring CNVs compared to those without CNVs
Summary
The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis is essential for normal human growth. Perturbations of this axis lead to growth hormone insensitivity (GHI, (MIM: 262500)) or IGF-1 insensitivity (MIM: 270450) (1). GHI is characterised by a triad of short stature (SS), functional IGF-1 deficiency and normal/ high GH levels. Several distinct phenotypic features facilitate the clinical recognition of these specific genetic defects. IGF-1 receptor (IGF1R) mutations are characterised by IGF-1 insensitivity causing impaired foetal and postnatal growth associated with high/normal IGF-1 levels and microcephaly/developmental delay (7). A significant proportion of patients with clear evidence of GHI and IGF-1 insensitivity remains without a genetic diagnosis despite extensive investigation
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