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

Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel

Lulu Yang  1 , Chenhui Zhang  2 , Wei Wang  1 , Junqi Wang  1 , Yuan Xiao  1 , Wenli Lu  1 , Xiaoyu Ma  1 , Lifen Chen  1 , Jihong Ni  1 , Defen Wang  1 , Jinxiu Shi  3 , Zhiya Dong  4
Affiliations

Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel

Lulu Yang et al. BMC Med Genet. .

Abstract

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.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Ruijin Hospital Ethics Committee Shanghai JiaoTong University School of Medicine. Informed written consent was obtained from participants or their guardians. In our study, 90 cases were under the age of 16; for these participants, their guardian provided written informed consent. In addition, one case of 16.7 years provided written informed consent.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
a: Short bone deformity of both hands, delayed development of osteophytes. b: Mild lateral curvature of the lumbar spine
Fig. 2
Fig. 2
a: Short bone deformity of both hands. b: Bilateral avascular necrosis of the femoral head
See this image and copyright information in PMC

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