title: Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect.
abstract: Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes.
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Minal J
authors.initials: MJ
authors.lastname: Menezes
authors.affiliation: Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Liang
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.affiliation: Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.affiliation: Department of Neurology, Sydney Children's Hospital, Randwick, NSW, Australia.
authors.forename: P Ian
authors.initials: PI
authors.lastname: Andrews
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Human Genetics Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Engel
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Human Genetics Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: john.christodoulou@health.nsw.gov.au.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China; The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics; D002675:Child, Preschool; D003094:Collagen / Q000235:genetics; D057210:Delayed Diagnosis; D016189:Dystrophin / Q000235:genetics; D059472:Exome; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D017240:Mitochondrial Myopathies / Q000175:diagnosis / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: C511692:DOK7 protein, human; D016189:Dystrophin; D009124:Muscle Proteins; D003094:Collagen; D000110:Acetylcholinesterase; C114027:COLQ protein, human
keywords: COLQ; Congenital myasthenia; DOK7; Duchenne muscular dystrophy; Mitochondrial respiratory chain; Mutation; Whole exome sequencing