title: Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance.
abstract: BACKGROUND
  Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases.
  
  
  METHODS
  We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease.
  
  
  RESULTS
  Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents.
  
  
  CONCLUSIONS
  De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novoDYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.
authors.affiliation: Department of Integrative Systems Biology, The George Washington University School of Medicine, Washington, DC; Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC.
authors.forename: Jaya
authors.initials: J
authors.lastname: Punetha
authors.affiliation: Hospital Nacional de Pediatria "J. P. Garrahan", Buenos Aires, Argentina.
authors.forename: Soledad
authors.initials: S
authors.lastname: Monges
authors.affiliation: Hospital Nacional de Pediatria "J. P. Garrahan", Buenos Aires, Argentina.
authors.forename: Maria Emilia
authors.initials: ME
authors.lastname: Franchi
authors.affiliation: Department of Integrative Systems Biology, The George Washington University School of Medicine, Washington, DC; Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC; Department of Neurology and Neurological Sciences, Stanford University Medical Center, Palo Alto, California. Electronic address: ctesiroc@hotmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Tesi-Rocha
mesh_terms: D002675:Child, Preschool; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D005260:Female; D006801:Humans; D038061:Lower Extremity Deformities, Congenital / Q000150:complications*; D009134:Muscular Atrophy, Spinal / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*
chemical_list: C511240:DYNC1H1 protein, human; D056445:Cytoplasmic Dyneins
keywords: Charcot-Marie-Tooth; DYNC1H1; SMA-LED; dSMA; distal spinal muscular atrophy; spinal muscular atrophy with lower extremity predominance; whole exome sequencing