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Clinical Utility of RNA Sequencing to Resolve Unusual GNE Myopathy with a Novel Promoter Deletion

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Clinical Utility of RNA Sequencing to Resolve Unusual GNE Myopathy with a Novel Promoter Deletion 11. de Seze MP, Rezzouk J, de Seze M, Uzel M, Lavignolle B, Midy D, et al. REFERENCES Does the motor branch of the long head of the triceps brachii arise 1. Hems TE, Mahmood F. Injuries of the terminal branches of the infra- from the radial nerve? An anatomic and electromyographic study. Surg clavicular brachial plexus: patterns of injury, management and out- Radiol Anat 2004;26(6):459–461. come. J Bone Joint Surg Br 2012;94:799–804. 12. Cartwright MS, Passmore LV, Yoon JS, Brown ME, Caress JB, Walker FO. 2. Atef A, El-Tantawy A, Gad H, Hefeda M. Prevalence of associated inju- Cross-sectional area reference values for nerve ultrasonography. Muscle ries after anterior shoulder dislocation: a prospective study. Int Orthop Nerve 2008;37(5):566–571. 2016;40:519–524. 13. Cartwright MS, Shin HW, Passmore LV, Walker FO. Ultrasonographic 3. Mitchell JJ, Chen C, Liechti DJ, Heare A, Chahla J, Bravman JT. Axillary reference values for assessing the normal median nerve in adults. nerve palsy and deltoid muscle atony. JBJS Rev 2017;5(7):e1. J Neuroimaging 2009;19(1):47–51. 4. Brown SA, Doolittle DA, Bohanon CJ, Jayaraj A, Naidu SG, Huettl EA, 14. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals et al. Quadrilateral space syndrome: the Mayo Clinic experience with a and patients with polyneuropathy: an ultrasound study. Muscle Nerve new classification system and case series. Mayo Clin Proc 2015;90(3): 2009;40(6):960–966. 382–394. 15. Cartwright MS, Mayans DR, Gillson NA, Griffin LP, Walker FO. Nerve 5. Maak TG, Osei D, Delos D, Taylor S, Warren RF, Weiland AJ. Periph- cross-sectional area in extremes of age. Muscle Nerve 2013;47(6): eral nerve injuries in sports-related surgery: presentation, evaluation, 890–893. and management: AAOS exhibit selection. J Bone Joint Surg Am 2012; 16. Won SJ, Kim BJ, Park KS, Kim SH, Yoon JS. Measurement of cross- 94(16):e121(1–10). sectional area of cervical roots and brachial plexus trunks. Muscle 6. Lee S, Saetia K, Saha S, Kline DG, Kim DH. Axillary nerve injury associ- Nerve 2012;46(5):711–716. ated with sports. Neurosurg Focus 2011;31(5):E10. 17. Qrimli M, Ebadi H, Breiner A, Siddiqui H, Alabdali M, Abraham A, 7. Boon A. Ultrasonography and electrodiagnosis: are they complemen- et al. Reference values for ultrasonography of peripheral nerves. Muscle tary techniques? PM R 2013;5(5 Suppl):S100–S106. Nerve 2016;53(4):538–544. 8. Gruber H, Peer S, Gruber L, Loescher W, Bauer T, Loizides A. Ultra- 18. Simone JP, Streubel PN, Sanchez-Sotelo J, Steinmann SP, Adams JE. sound imaging of the axillary nerve and its role in the diagnosis of trau- Change in the distance from the axillary nerve to the glenohumeral matic impairment. Ultraschall Med 2014;35(4):332–338. joint with shoulder external rotation or abduction position. Hand 9. Stecco C, Gagliano G, Lancerotto L, Tiengo C, Macchi V, Porzionato A, (N Y) 2017;12(4):395–400. et al. Surgical anatomy of the axillary nerve and its implication in the 19. James J, Sutton LG, Werner FW, Basu N, Allison MA, Palmer AK. Mor- transdeltoid approaches to the shoulder. J Shoulder Elbow Surg 2010; phology of the cubital tunnel: an anatomical and biomechanical study 19(8):1166–1174. with implications for treatment of ulnar nerve compression. J Hand 10. Leechavengvongs S, Teerawutthichaikit T, Witoonchart K, Surg Am 2011;36(12):1988–1995. Uerpairojkit C, Malungpaishrope K, Suppauksorn S, et al. Surgical anat- 20. Thoirs K, Williams MA, Phillips M. Ultrasonographic measurements of omy of the axillary nerve branches to the deltoid muscle. Clin Anat 2015; the ulnar nerve at the elbow: role of confounders. J Ultrasound Med – 28(1):118 122. 2008;27(5):737–743. CLINICAL UTILITY OF RNA SEQUENCING TO RESOLVE UNUSUAL GNE MYOPATHY WITH A NOVEL PROMOTER DELETION SAMYA CHAKRAVORTY, PHD ,1 KIERA BERGER, BS,2 DALIA ARAFAT, MS,2 BABI RAMESH REDDY NALLAMILLI, PHD,1 HARI PRASANNA SUBRAMANIAN, MS,2 SOUMYA JOSEPH, PHD,3 MARY E. ANDERSON, MS,3 KEVIN P. CAMPBELL, PHD,3 JONATHAN GLASS, MD,4 GREG GIBSON, PHD,2 and MADHURI HEGDE, PHD1,5 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 Accepted 12 April 2019 ABSTRACT: Introduction: UDP N-acetylglucosamine2-epimerase/ both the diagnosis and a better understanding of the genotype- Results: fi N-acetylmannosamine-kinase (GNE) gene mutations can cause phenotype relationship. We identi ed a novel 7.08 kb path- GNE mostly autosomal-recessive myopathy with juvenile-onset known as ogenic deletion upstream of using array comparative genomic hereditary inclusion-body myopathy (HIBM). Methods: We describe hybridization (aCGH) and a common Val727Met variant. Using RNA- a family of a patient showing an unusual HIBM with both vacuolar seq, we found only monoallelic (Val727Met-allele) expression, lead- GNE α myopathy and myositis without quadriceps-sparing, hindering diag- ing to ~50% reduction in muscle. Importantly, -dystroglycan is nosis. We show how genetic testing with functional assays, clinical hypoglycosylated in the patient muscle, suggesting HIBM could be a “ ” Conclusions: transcriptome sequencing (RNA-seq) in particular, helped facilitate dystroglycanopathy. Our study shows the impor- tance of considering aCGH for GNE-myopathies, and the poten- tial of RNA-seq for faster, definitive molecular diagnosis of Additional supporting information may be found in the online version of unusual myopathies. this article. Muscle Nerve 60:98–103, 2019 Key words: aCGH, GNE myopathy (HIBM), molecular diagnostics, myosi- tis, next generation sequencing, transcriptome sequencing (RNA-seq) This work was also supported by Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (1U54NS053672) Funding: This work was supported by the Muscular Dystrophy Associa- tion grant MDA578400 to S.C. and grant MDA418496 to M.H. To enhance molecular diagnostic yield in neuro- Conflicts of Interest: None of the authors has any conflict of interest to muscular disorders (NMDs), functional assays down- – disclose. stream of genomic DNA1 4 is recommended by the Correspondence to: S. Chakravorty; e-mail: [email protected]. American College of Medical Genetics and Geno- and M. Hegde; e-mail: [email protected] mics (ACMG).5 GNE-myopathy (OMIM #605820) or © 2019 Wiley Periodicals, Inc. Published online 16 April 2019 in Wiley Online Library hereditary inclusion-body myopathy (HIBM) is a vac- (wileyonlinelibrary.com). DOI 10.1002/mus.26486 uolar myopathy generally sparing the quadriceps. It 98 Clinical Research Short Reports MUSCLE & NERVE July 2019 is a rare, recessive, inherited degenerative skeletal kinase-domain crystal-structure was performed. For methods muscle disorder caused by GNE gene (MIM# 603824; details, see Supplementary Methods, which are available online. NCBI Gene ID: 10020; NC_000009.12) variants with - – early-adult onset.6 8 The GNE enzyme catalyzes RESULTS the first 2 rate-limiting steps in the biosynthesis of Clinical Phenotype. The patient was a 21-year-old man, 5-N-acetylneuraminic acid (Neu5Ac)9,10 found as the ethnically Indian-Guyanese, with progressive muscle- terminal glycans on various glycoproteins/glycolipids, weakness without any cardiac or respiratory comorbidity. such as the sarcoglycans and dystroglycan (DG), func- Symptoms began at age 20 years with asymmetric leg pain tioning in variety of cellular pathways.11 and weakness, initially with bilateral-foot-drop and mild Our understanding of the molecular basis of GNE (Medical Research Council 4/5) weakness in the quadri- myopathy is unclear.12,13 Here,wedescribethelessons ceps, followed by rapidly progressive and severe bilateral learned by using functional genomic approaches to lower extremity distal weakness, additional quadriceps characterize an unusual GNE myopathy in a family weakness, and upper extremity weakness in the deltoids fi fl with a novel deletion variant in which relative quadri- and the long- nger- exors. There was no facial or bulbar fl cepssparinginassociationwithbothvacuolarmyopa- weakness and tendon re exes were reduced throughout. thy and myositis made diagnosis challenging. Needle electromyography of the quadriceps, tibialis anterior, iliopsoas, and medial gastrocnemius muscles demonstrated abnormal spontaneous activity (fibrillation MATERIALS AND METHODS potentials and positive sharp waves) and early motor unit All protocols were approved by institutional IRB with written potential recruitment, compatiblewithmultipletypesof consents and are presented here in chronological order. First, myopathies. There was no family history of neuromuscu- trio (patient and parents) exome sequencing and simultaneous lar disease. patient muscle biopsy immunohistochemistry, and then RNA sequencing of the biopsy, were performed, which prompted us to Quadriceps Showed Unusual HIBM: Both Vacuolar and do array comparative genomic hybridization (aCGH) to identify Inflammatory Myopathy. Quadriceps biopsy (Fig. 1) any deletions/duplications. Immunoblotting was then done using showed increased fiber-size variability with both muscle- biopsy to identify any glycosylation defect related to the HIBM fi fl pathophysiology. Gene ontology-pathway analysis14 led to further ber necrosis and perivascular in ammation. Promi- understanding of patient muscle glycosylation defects. Molecular- nent rimmed vacuoles were seen on modified Gomori dynamics (MD) simulation of the V727M variant on the GNE trichromethatwerepositivebyimmunohistochemistry FIGURE 1. Muscle biopsy showing central and sub-sarcolemmal vacuoles in hemotoxylin and eosin (H&E) (top panel left), which demon- strates red “rimming” with modified Gomori trichrome (top center panel). An example of inflammation is seen in the top right panel (cir- cled).
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