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Original Investigation |

Mutations in VRK1 Associated With Complex Motor and Sensory Axonal Neuropathy Plus Microcephaly

Claudia Gonzaga-Jauregui, PhD1; Timothy Lotze, MD2; Leila Jamal, ScM3; Samantha Penney, MSc1,2; Ian M. Campbell, BS1; Davut Pehlivan, MD1; Jill V. Hunter, MBBS2; Suzanne L. Woodbury, MD2; Gerald Raymond, MD4; Adekunle M. Adesina, MD, PhD2; Shalini N. Jhangiani, MSc5; Jeffrey G. Reid, PhD5; Donna M. Muzny, MSc5; Eric Boerwinkle, PhD5,6; James R. Lupski, MD, PhD, DSc1,2,5; Richard A. Gibbs, PhD1,5; Wojciech Wiszniewski, MD, PhD1
[+] Author Affiliations
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
2Texas Children’s Hospital, Houston
3Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland
4Department of Neurology, University of Minnesota, Minneapolis
5Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
6Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston
JAMA Neurol. 2013;70(12):1491-1498. doi:10.1001/jamaneurol.2013.4598.
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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.

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Figure 1.
Mutations in VRK1 in 2 Sisters With Microcephaly and Peripheral Neuropathy

A, Brain magnetic resonance imaging studies showed microcephaly, a simplified gyral pattern, and normal pons and cerebellum at ages 4 years and 1 year in both affected siblings BAB3022 and BAB3280, respectively. B, Profound nonprogressive microcephaly was documented for all affected individuals. Upper panels show fronto-occipital circumference (FOC) measurements for both patients. Solid black lines indicate the mean FOC for age; dashed lines, ±2-SD FOC values for age; red and blue lines, corresponding FOC trend lines for each patient (red, BAB3280; blue, BAB3022); and dots, individual measurements at specific ages of the respective patients. Lower panels show standard deviations (SDs) below the mean for head circumference measurements in the 2 patients. C, Electron microscopy of a sural nerve biopsy specimen demonstrated the loss of large myelinated fibers, increased endoneural collagen, and rare degenerating myelin (original magnification ×1500). D, Hematoxylin-eosin staining of a muscle biopsy specimen showed neurogenic muscle atrophy with spinal muscular atrophy–like atrophy of large fascicles alternating with well-preserved nonatrophic fascicles (original magnification ×200). E, Family pedigree shows segregation of disease-causing VRK1 mutations, p.V236M and p.R89Q, with the neurological phenotype; patients BAB3280 and BAB3022 are compound heterozygotes for p.V236M and p.R89Q, their father (BAB3024) is a carrier for p.R89Q, their mother (BAB3023) is a carrier of p.V236M, and their unaffected sister (BAB3693) has no VRK1 mutant alleles.

Graphic Jump Location
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Figure 2.
Male Patient With Homozygous Nonsense Mutation in VRK1

A, In patient BAB5311, brain magnetic resonance imaging revealed microcephaly, a simplified gyral pattern, normal pons and cerebellar hemispheres, and vermian hypoplasia. B, He showed nonprogressive microcephaly, which was first noted by ultrasonography in utero at 30 weeks’ gestation and was recorded after birth. Upper panel shows fronto-occipital circumference (FOC) measurements. Solid black line without dots indicates the mean FOC for age; dashed lines, ±2-SD FOC values for age; line with dots, corresponding FOC trend line for the patient; and dots, individual measurements at specific ages of the patient. Lower panel shows standard deviations (SDs) below the mean for head circumference measurements. C, Family pedigree shows segregation of the nonsense p.R358X mutation; the affected proband (BAB5311) is homozygous, while both his parents (BAB5321 and BAB5320) and sister (BAB5322) are heterozygous carriers.

Graphic Jump Location
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Figure 3.
High-Resolution Single-Nucleotide Polymorphism Array Data for Chromosome 14 in Affected Patient BAB5311 and His Parents BAB5320 and BAB5321

The data show that both unaffected parents of the patient are heterozygous, while the patient is homozygous for the common haplotype region in which the p.R358X mutation occurred. The region, which is approximately 500 673 base pairs, includes VRK1 only. In the upper plots, 1 pixel indicates 3 kilobases; in the lower plots, 1 pixel indicates 330 base pairs.

Graphic Jump Location




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