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J Hum Genet. 2017 Feb;62(2):159-166. doi: 10.1038/jhg.2016.134. Epub 2016 Nov 10.

Missing genetic variations in GNE myopathy: rearrangement hotspots encompassing 5'UTR and founder allele.

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Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo, Japan.
Department of Genome Medicine Development, Medical Genome Center (MGC), National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
Department of Neurology, Bangalore, India.
Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bangalore, India.
Department of Neurology, Kansai Electric Power Hospital, Osaka, Japan.
Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Neurology, Akita University Graduate School of Medicine, Akita, Japan.
Department of Neurology, Nagano Red Cross Hospital, Nagano, Japan.
Shizusato Shinryojo, Gifu, Japan.
Department of Neurology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Department of Neurology, Ogaki Municipal Hospital, Gifu, Japan.


GNE myopathy is an autosomal recessive distal myopathy caused by loss-of-function mutations in the GNE gene, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in sialic-acid biosynthesis. By comprehensive screening of manifesting patients using a fine-mapped targeted next-generation sequencing (NGS), we identified copy number variations (CNVs) in 13 patients from 11 unrelated families. The nine unique CNVs largely vary in size from 0.3 to 72 kb. Over half of the cases carry different deletions spanning merely exon 2, which contains the 5' untranslated region (5'UTR) of the muscle major transcript hGNE1. Of most unique CNVs, either the telomeric or the centromeric breakpoint locates within intron 2, indicating rearrangement hotspots. Haplotype analysis suggested the existence of a founder allele with exon 2 deletion. The breakpoints for all CNVs were determined by long-range PCR and sequencing. All of the breakpoints of gross deletion/duplications reside within directly oriented pairs of Alu repeats. The results of this study firstly widen the spectra of mutations to CNVs encompassing 5'UTR, underscoring the pivotal role of the hGNE1 transcript. Alu-mediated non-recurrent CNVs may have been overlooked in a wide variety of recessive phenotypes, especially in those associated with genomic Alu-rich genes such as GNE.

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