title: Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia.
abstract: BACKGROUND
  Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships.
  
  
  METHODS
  Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene.
  
  
  RESULTS
  Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype.
  
  
  CONCLUSIONS
  We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme.
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, UK School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Christopher M
authors.identifier: http://orcid.org/0000-0003-2371-1844
authors.initials: CM
authors.lastname: Watson
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, UK School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Crinnion
authors.affiliation: Genomic Medicine, Manchester Academic Health Science Centre, The University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Murphy
authors.affiliation: Department of Paediatric Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Newbould
authors.affiliation: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Harrison
authors.affiliation: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lascelles
authors.affiliation: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Agne
authors.initials: A
authors.lastname: Antanaviciute
authors.affiliation: School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, UK School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, UK School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, UK.
authors.forename: Audrey
authors.initials: A
authors.lastname: Smith
mesh_terms: D037881:Aborted Fetus; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D009154:Mutation; D017570:MyoD Protein / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein
keywords: <i>MYOD1</i>; exome sequencing; fetal akinesia; lung hypoplasia; perinatal lethal