The following new article has just been published in Orphanet Journal of Rare Diseases

Research

Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth

Todd E, Yau K, Ong R, Slee J, McGillivray G, Barnett C, Haliloglu G, Talim B, Akcoren Z, Kariminejad A, Cairns A, Clarke N, Freckmann M, Romero N, Williams D, Sewry CA, Colley A, Ryan M, Kiraly-Borri C, Sivadorai P, Allcock R, Beeson D, Maxwell S, Davis M, Laing N, Ravenscroft G

Orphanet Journal of Rare Diseases 2015, 10 :148 (17 November 2015)

Abstract | Full Text | PDF

Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth

Emily J. Todd¹, Kyle S. Yau¹, Royston Ong¹, Jennie Slee², George McGillivray³,Christopher P. Barnett⁴, Goknur Haliloglu⁵, Beril Talim⁶, Zuhal Akcoren⁶, Ariana Kariminejad⁷, Anita Cairns⁸, Nigel F. Clarke¹⁰⁹, Mary-Louise Freckmann¹¹, Norma B. Romero¹², Denise Williams¹³¹⁴, Caroline A Sewry¹³¹⁴, Alison Colley¹⁵, Monique M. Ryan¹⁶, Cathy Kiraly-Borri¹⁷, Padma Sivadorai¹⁸, Richard J.N. Allcock¹⁹, David Beeson²⁰,Susan Maxwell²⁰, Mark R. Davis¹⁸, Nigel G. Laing¹¹⁸ and Gianina Ravenscroft¹^*

*Corresponding author: Gianina Ravenscroftgina.ravenscroft@perkins.uwa.edu.au

Author Affiliations

¹Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands 6009, , WA, Australia

²Genetic Services of Western Australia, King Edward Memorial Hospital, Perth 6000, , WA, Australia

³Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville 3052, , VIC, Australia

⁴Paediatric and Reproductive Genetics Unit, South Australia Clinical Genetics Service, Women’s and Children’s Hospital, North Adelaide 5006, , SA, Australia

⁵Department of Pediatric Neurology, Hacettepe University Children’s Hospital, Ankara 06100, Turkey

⁶Pediatric Pathology Unit, Hacettepe University Children’s Hospital, Ankara 06100, Turkey

⁷Kariminejad-Najmabadi Pathology and Genetics Centre, Tehran 14656, Iran

⁸Royal Children’s Hospital, Herston Road, Herson 4029, , QLD, Australia

⁹Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Sydney 2145, , NSW, Australia

¹⁰Discipline of Paediatrics and Child Health, University of Sydney, Sydney 2006, , NSW, Australia

¹¹Sydney Children’s Hospital, High Street, Randwick 2031, , NSW, Australia

¹²Unitè de Morphologie Neuromusculaire, Institut de Myologie, Institut National de la Santè et de la Recherche Mèdicale, Paris 75651, France

¹³Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UK

¹⁴Wolfson Centre for Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK

¹⁵Department of Clinical Genetics, South Western Sydney Local Health District, Liverpool 1871, , NSW, Australia

¹⁶Department of Neurology, The Royal Children’s Hospital, Melbourne 3000, , VIC, Australia

¹⁷Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Subiaco 6008, , WA, Australia

¹⁸Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands 6009, , WA, Australia

¹⁹Lotterywest State Biomedical Facility Genomics and School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6000, , WA, Australia

²⁰Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK

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Orphanet Journal of Rare Diseases 2015, 10:148 doi:10.1186/s13023-015-0364-0

The electronic version of this article is the complete one and can be found online at:http://www.ojrd.com/content/10/1/148

Received:	20 August 2015
Accepted:	2 November 2015
Published:	17 November 2015

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

Background

Fetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual’s DNA can now be analysed through “whole” exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these.

Methods

Genomic DNA samples from 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated families were subjected to next generation sequencing. Clinical features and diagnoses for each patient were supplied by referring clinicians. Genomic DNA was used for either whole exome sequencing or a custom-designed neuromuscular sub-exomic supercapture array containing 277 genes responsible for various neuromuscular diseases. Candidate disease-causing variants were investigated and confirmed using Sanger sequencing. Some of the cases within this cohort study have been published previously as separate studies.

Results

A conclusive genetic diagnosis was achieved for 18 of the 38 families. Within this cohort, mutations were found in eight previously known neuromuscular disease genes (CHRND, CHNRG, ECEL1,GBE1, MTM1, MYH3, NEB and RYR1) and four novel neuromuscular disease genes were identified and have been published as separate reports (GPR126, KLHL40, KLHL41 and SPEG). In addition, novel mutations were identified in CHRND, KLHL40, NEB and RYR1. Autosomal dominant, autosomal recessive, X-linked, and de novo modes of inheritance were observed.

Conclusions

By using next generation sequencing on a cohort of 38 unrelated families with fetal akinesia/hypokinesia, arthrogryposis, or severe congenital myopathy we therefore obtained a genetic diagnosis for 47 % of families. This study highlights the power and capacity of next generation sequencing (i) to determine the aetiology of genetically heterogeneous neuromuscular diseases, (ii) to identify novel disease genes in small pedigrees or isolated cases and (iii) to refine the interplay between genetic diagnosis and clinical evaluation and management.