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Eur J Hum Genet. 2014 May;22(5):602-9. doi: 10.1038/ejhg.2013.203. Epub 2013 Sep 25.

Copy number variants in patients with short stature.

Author information

  • 11] Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands [2] Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands [3] Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 2Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • 3Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 4Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • 5Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
  • 6Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.
  • 7Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
  • 8Department of Pediatrics, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
  • 9Institute of Maternal and Child Disease, University of Chile, Santiago, Chile.
  • 10Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.

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