title: A Large Deletion Affecting TPM3, Causing Severe Nemaline Myopathy.
abstract: OBJECTIVE
  Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1. All previously identified disease-causing variants are point mutations including missense, nonsense and splice-site variants. The aim of the study was to identify the disease-causing gene in this patient and verify the NM diagnosis.
  
  
  METHODS
  Mutation analysis methods include our self-designed nemaline myopathy array, The Nemaline Myopathy Comparative Genomic Hybridisation Array (NM-CGH array), whole-genome array-CGH, dHPLC, Sanger sequencing and whole-exome sequencing. The diagnostic muscle biopsy was investigated further by routine histopathological methods.
  
  
  RESULTS
  We present here the first large (17-21 kb) aberration in the α-tropomyosinslow gene (TPM3), identified using the NM-CGH array. This homozygous deletion removes the exons 1a and 2b as well as the promoter of the TPM3 isoform encoding Tpm3.12st. The severe phenotype included paucity of movement, proximal and axial weakness and feeding difficulties requiring nasogastric tube feeding. The infant died at the age of 17.5 months. Muscle biopsy showed variation in fibre size and rods in a population of hypotrophic muscle fibres expressing slow myosin, often with internal nuclei, and abnormal immunolabelling revealing many hybrid fibres.
  
  
  CONCLUSIONS
  This is the only copy number variation we have identified in any NM gene other than nebulin (NEB), suggesting that large deletions or duplications in these genes are very rare, yet possible, causes of NM.
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Kiiski
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: V-L
authors.initials: VL
authors.lastname: Lehtokari
authors.affiliation: Great Ormond Street Hospital, London, UK.
authors.forename: A Y
authors.initials: AY
authors.lastname: Manzur
authors.affiliation: Great Ormond Street Hospital, London, UK.|Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Sewry
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Zaharieva
authors.affiliation: Great Ormond Street Hospital, London, UK.|Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.|Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Pelin
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Wallgren-Pettersson
keywords: DNA copy number variation; NM-CGH array; Nemaline myopathy; TPM3; alpha-tropomyosin; array comparative genomic hybridization; deletion mutation; exome sequencing; rod myopathy