title: Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.
abstract: BACKGROUND
  Leukodystrophies are a large group of inherited diseases of central nervous system myelin. There are few treatments, and most patients do not receive a final genetic diagnosis.
  
  
  METHODS
  We report a novel presentation of a female child with hypotonia, global developmental delay, and rotatory nystagmus. Brain MRI demonstrated profound hypomyelination and minimal or no atrophy in the brain stem or cerebellum.
  
  
  RESULTS
  Extensive testing failed to yield a diagnosis until clinical whole-exome sequencing revealed a novel pathogenic mutation in the β-tubulin gene TUBB4A. TUBB4A is a cause of hereditary dystonia type 4 and has recently been reported to cause hypomyelination with atrophy of the basal ganglia and cerebellum.
  
  
  CONCLUSIONS
  This report expands the phenotypic spectrum of TUBB4A-associated neurological diseases to include static hypomyelinating leukodystrophy and supports the clinical relevance of next-generation sequencing diagnosis approaches.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Purnell
authors.affiliation: Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.affiliation: Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, Utah. Electronic address: joshua.bonkowsky@hsc.utah.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Bonkowsky
mesh_terms: D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010641:Phenotype; D014404:Tubulin / Q000235:genetics*
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin
keywords: TUBB4A; hypomyelination; leukodystrophy; whole-exome sequencing
references.citation: Neurology. 2010 Aug 24;75(8):718-25
references.pmid: 20660364
references.citation: J Mol Biol. 2001 Nov 9;313(5):1045-57
references.pmid: 11700061
references.citation: Neurology. 2007 Jul 10;69(2):166-71
references.pmid: 17620549
references.citation: Ann Neurol. 2013 Apr;73(4):546-53
references.pmid: 23424103
references.citation: Am J Hum Genet. 2013 May 2;92(5):767-73
references.pmid: 23582646
references.citation: Neurology. 2009 Feb 24;72(8):750-9
references.pmid: 19237705
references.citation: J Child Neurol. 2003 Sep;18(9):578-90
references.pmid: 14572135
references.citation: N Engl J Med. 2013 Oct 17;369(16):1502-11
references.pmid: 24088041
references.citation: Pediatr Neurol. 2001 Jan;24(1):11-24
references.pmid: 11182276
references.citation: Adv Exp Med Biol. 2012;724:154-71
references.pmid: 22411242
references.citation: Expert Rev Neurother. 2011 Oct;11(10):1485-96
references.pmid: 21955203