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

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

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Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Tokyo 157-8535, Japan.
Department of Pediatrics, Shizuoka City Shimizu Hospital, Shizuoka 424-8636, Japan.
Department of Pediatrics, Okayama Saiseikai General Hospital, Okayama 700-8511, Japan.
Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
Department of Pediatrics, Omihachiman Community Medical Center, Omihachiman 523-0082, Japan.
Department of Gastroenterology and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi 594-1101, Japan.
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan.
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Institute director, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Tanaka Growth Clinic, Tokyo 158-0097, Japan.


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.


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

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