Pathogenic Gene Screening in 91 Chinese Patients With Short Stature of Unknown Etiology With a Targeted Next-Generation Sequencing Panel

BMC Med Genet. 2018 Dec 12;19(1):212. doi: 10.1186/s12881-018-0730-6.


Background: Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening.

Methods: Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed.

Results: The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia.

Conclusions: Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.

Keywords: Next generation sequencing (NGS); Pathogenic genes; Short stature; Targeted panel; Unknown etiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aggrecans / genetics
  • Arthritis / diagnosis
  • Arthritis / ethnology
  • Arthritis / genetics*
  • Arthritis / pathology
  • Asian Continental Ancestry Group
  • Cartilage Oligomeric Matrix Protein / genetics
  • Child
  • Child, Preschool
  • Collagen Type II / genetics
  • Connective Tissue Diseases / diagnosis
  • Connective Tissue Diseases / ethnology
  • Connective Tissue Diseases / genetics*
  • Connective Tissue Diseases / pathology
  • Dwarfism / diagnosis
  • Dwarfism / ethnology
  • Dwarfism / genetics*
  • Dwarfism / pathology
  • Female
  • Gene Expression
  • Genetic Testing / methods
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / ethnology
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • High-Throughput Nucleotide Sequencing
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Mutation*
  • Noonan Syndrome / diagnosis
  • Noonan Syndrome / ethnology
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / pathology
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / ethnology
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Retinal Detachment / diagnosis
  • Retinal Detachment / ethnology
  • Retinal Detachment / genetics*
  • Retinal Detachment / pathology
  • SOS1 Protein / genetics
  • Transcription Factors / genetics


  • ACAN protein, human
  • Aggrecans
  • COL2A1 protein, human
  • Cartilage Oligomeric Matrix Protein
  • Collagen Type II
  • Comp protein, mouse
  • HOXD13 protein, human
  • Homeodomain Proteins
  • SOS1 Protein
  • Transcription Factors
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11

Supplementary concepts

  • Stickler syndrome, type 1