Department of Human Genetics, Emory University School of Medicine, Whitehead Building Suite 301, 615 Michael Street NE, Georgia, USA.
Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.
Muscle Nerve. 2019 Jul;60(1):98-103. doi: 10.1002/mus.26486. Epub 2019 Apr 29.
UDP N-acetylglucosamine2-epimerase/N-acetylmannosamine-kinase (GNE) gene mutations can cause mostly autosomal-recessive myopathy with juvenile-onset known as hereditary inclusion-body myopathy (HIBM).
We describe a family of a patient showing an unusual HIBM with both vacuolar myopathy and myositis without quadriceps-sparing, hindering diagnosis. We show how genetic testing with functional assays, clinical transcriptome sequencing (RNA-seq) in particular, helped facilitate both the diagnosis and a better understanding of the genotype-phenotype relationship.
We identified a novel 7.08 kb pathogenic deletion upstream of GNE using array comparative genomic hybridization (aCGH) and a common Val727Met variant. Using RNA-seq, we found only monoallelic (Val727Met-allele) expression, leading to ~50% GNE reduction in muscle. Importantly, α-dystroglycan is hypoglycosylated in the patient muscle, suggesting HIBM could be a "dystroglycanopathy."
Our study shows the importance of considering aCGH for GNE-myopathies, and the potential of RNA-seq for faster, definitive molecular diagnosis of unusual myopathies. Muscle Nerve, 2019.
UDP-N-乙酰氨基葡萄糖 2-差向异构酶/N-乙酰氨基葡萄糖-激酶（GNE）基因突变可导致大多数常染色体隐性遗传肌病，青少年起病，称为遗传性包涵体肌病（HIBM）。
我们描述了一个家系的患者表现出一种不寻常的 HIBM，既有空泡性肌病又有肌炎，没有股四头肌保留，这妨碍了诊断。我们展示了如何通过功能测定的基因检测，特别是临床转录组测序（RNA-seq），有助于诊断和更好地理解基因型-表型关系。
我们使用阵列比较基因组杂交（aCGH）和常见的 Val727Met 变体发现了一个新的位于 GNE 上游的 7.08 kb 致病性缺失。使用 RNA-seq，我们发现只有单等位基因（Val727Met-等位基因）表达，导致肌肉中 GNE 减少约 50%。重要的是，患者肌肉中的α-肌聚糖聚糖糖基化不足，提示 HIBM 可能是一种“肌聚糖病”。
我们的研究表明，对于 GNE 肌病，考虑使用 aCGH 非常重要，而 RNA-seq 对于快速、明确诊断不寻常肌病具有潜在的应用价值。《肌肉神经》，2019 年。
