title: Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly.
abstract: OBJECTIVE
  Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.
  
  
  OBJECTIVE
  To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.
  
  
  METHODS
  Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.
  
  
  METHODS
  Whole-genome and whole-exome sequencing identified the variants responsible for the patients' clinical phenotype.
  
  
  RESULTS
  We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.
  
  
  CONCLUSIONS
  We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Texas Children's Hospital, Houston.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lotze
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
authors.forename: Leila
authors.initials: L
authors.lastname: Jamal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Texas Children's Hospital, Houston.
authors.forename: Samantha
authors.initials: S
authors.lastname: Penney
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Texas Children's Hospital, Houston.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: Texas Children's Hospital, Houston.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Woodbury
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis.
authors.forename: Gerald
authors.initials: G
authors.lastname: Raymond
authors.affiliation: Texas Children's Hospital, Houston.
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas6Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Texas Children's Hospital, Houston5Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas5Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human