Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly

Claudia Gonzaga-Jauregui, Timothy Lotze, Leila Jamal, Samantha Penney, Ian M. Campbell, Davut Pehlivan, Jill V. Hunter, Suzanne L. Woodbury, Gerald Raymond, Adekunle M. Adesina, Shalini N. Jhangiani, Jeffrey G. Reid, Donna M. Muzny, Eric Boerwinkle, James R. Lupski, Richard A. Gibbs, Wojciech Wiszniewski

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Abstract

IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

Original languageEnglish (US)
Pages (from-to)1491-1498
Number of pages8
JournalJAMA neurology
Volume70
Issue number12
DOIs
Publication statusPublished - Dec 2013

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All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Gonzaga-Jauregui, C., Lotze, T., Jamal, L., Penney, S., Campbell, I. M., Pehlivan, D., ... Wiszniewski, W. (2013). Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA neurology, 70(12), 1491-1498. https://doi.org/10.1001/jamaneurol.2013.4598