Samya Chakravorty1, Kiera Berger2, Dalia Arafat2, Babi Ramesh Reddy Nallamilli1, Hari Prasanna Subramanian2, Soumya Joseph3, Mary E Anderson3, Kevin P Campbell3, Jonathan Glass4, Greg Gibson2, Madhuri Hegde1,5. 1. Department of Human Genetics, Emory University School of Medicine, Whitehead Building Suite 301, 615 Michael Street NE, Georgia, USA. 2. Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA. 3. Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, 52242, USA. 4. Department of Neurology and Pathology, Emory University School of Medicine, Atlanta, Georgia, USA. 5. Global Laboratory Services/Diagnostics, Perkin Elmer, Waltham, Massachusetts, USA.
Abstract
INTRODUCTION: 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). METHODS: 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. RESULTS: 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." CONCLUSIONS: 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.
INTRODUCTION: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). METHODS: 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. RESULTS: 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." CONCLUSIONS: 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.
Authors: Marco Savarese; Jaakko Sarparanta; Anna Vihola; Per Harald Jonson; Mridul Johari; Salla Rusanen; Peter Hackman; Bjarne Udd Journal: Acta Myol Date: 2020-12-01