Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity

in European Journal of Endocrinology
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  • 1 Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK
  • 2 Centre for Translational Bioinformatics, Queen Mary University of London, London, UK
  • 3 NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • 4 University College London, Great Ormond Street Institute of Child Health, London, UK
  • 5 University Hospitals of Leicester NHS Trust, Leicester, UK
  • 6 The University of Sheffield Faculty of Medicine, Dentistry and Health, Sheffield, UK
  • 7 Department of Pediatrics, Endocrinology and Diabetes with a Cardiology Unit, Medical University of Bialystok, Bialystok, Poland
  • 8 Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, United Arab Emirates
  • 9 Mubarak Al-kabeer Hospital, Jabriya, Kuwait
  • 10 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  • 11 Royal Hospital for Children, Glasgow, UK
  • 12 Viapath, Guy’s Hospital, London, UK
  • 13 Addenbrookes Hospital, Cambridge, UK
  • 14 Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Correspondence should be addressed to H L Storr; Email: h.l.storr@qmul.ac.uk
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Objective

Copy 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 methods

Array 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.

Results

Both 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.

Conclusions

Our 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.

 

     European Society of Endocrinology

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