The etiology of idiopathic short stature (ISS) and Leri–Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.
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We thank Drs M Toki and M Izawa for providing samples and clinical information of their patients. This study was supported by JCR Pharmaceuticals. The sponsor had no role in the study design, in the collection, analysis or interpretation of data, in the writing of the report or in the decision to submit the report for publication.
Maki Fukami has received a research grant from JCR pharmaceuticals. The remaining authors declare no conflict of interest.
The Japanese SHOX Study Group M. Adachi (Kanagawa Children’s Medical Center), T. Tajima (Hokkaido University), T. Tanaka (Tanaka Growth Clinic), O. Arisaka and S. Koyama (Dokkyo Medical University), T. Hamajima (Aichi Children’s Health and Medical Center), O. Nose (Nose Clinic), K. Ozono and N. Namba (Osaka University), K. Nagasaki (Niigata University), T. Kamimaki (Shizuoka City Shimizu Hospital), S. Kanzaki (Tottori University), T. Ogata (Hamamatsu University School of Medicine), H. Tanaka (Okayama Saiseikai General Hospital), Y. Hasegawa (Tokyo Metropolitan Children’s Medical Center), K. Kobayashi (University of Yamanashi), S. Dateki (Nagasaki University), H. Mabe (Kumamoto University), I. Fujiwara (Tohoku University), S. Ida (Osaka Medical Center and Research Institute for Maternal and Child Health), T. Hasegawa (Keio University), A. Uematsu (Shizuoka Children’s Hospital), K. Kashimada (Tokyo Medical Dental University), K. Onigata (Shimane University), K. Miyako (Fukuoka Children’s Hospital), S. Yokoya and R. Horikawa (National Center for Child Health and Development), and M. Fukami (National Research Institute for Child Health and Development).
Supplementary Information accompanies the paper on Journal of Human Genetics website .
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Shima, H., Tanaka, T., Kamimaki, T. et al. Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri–Weill dyschondrosteosis. J Hum Genet 61, 585–591 (2016) doi:10.1038/jhg.2016.18
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