Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

Endocr J. 2017 Oct 28;64(10):947-954. doi: 10.1507/endocrj.EJ17-0150. Epub 2017 Aug 3.

Abstract

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

Keywords: ACAN; Growth hormone - insulin-like grotwh factor 1; Idiopathic short stature; Mutation.

MeSH terms

  • Aggrecans / chemistry
  • Aggrecans / genetics*
  • Aggrecans / metabolism
  • Amino Acid Substitution
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Child
  • Child, Preschool
  • Cohort Studies
  • Computational Biology
  • Databases, Genetic
  • Expert Systems
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Glycoproteins / chemistry
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Growth Disorders / blood
  • Growth Disorders / genetics*
  • Growth Disorders / metabolism
  • Growth Disorders / physiopathology
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Japan
  • Male
  • Mutation*
  • Receptor, Fibroblast Growth Factor, Type 3 / chemistry
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Receptor, IGF Type 1
  • Receptors, Neuropeptide / chemistry
  • Receptors, Neuropeptide / genetics*
  • Receptors, Neuropeptide / metabolism
  • Receptors, Pituitary Hormone-Regulating Hormone / chemistry
  • Receptors, Pituitary Hormone-Regulating Hormone / genetics*
  • Receptors, Pituitary Hormone-Regulating Hormone / metabolism
  • Receptors, Somatomedin / chemistry
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism
  • STAT5 Transcription Factor / chemistry
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism

Substances

  • ACAN protein, human
  • Aggrecans
  • Carrier Proteins
  • Glycoproteins
  • IGF1R protein, human
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • Receptors, Somatomedin
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • insulin-like growth factor binding protein, acid labile subunit
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, IGF Type 1
  • somatotropin releasing hormone receptor
  • somatotropin-binding protein