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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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
StatePublished - 2013
Externally publishedYes

Fingerprint

Vaccinia
Microcephaly
Phosphotransferases
Exome
Phenotype
Mutation
Alleles
Genomics
Genes
Genome
Pediatric Hospitals
Nonsense Codon
Tertiary Healthcare
Rare Diseases
Haplotypes
Nervous System
Single Nucleotide Polymorphism
Biomedical Research
Siblings
Cell Cycle

ASJC Scopus subject areas

  • 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

Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. / Gonzaga-Jauregui, Claudia; Lotze, Timothy; Jamal, Leila; Penney, Samantha; Campbell, Ian M.; Pehlivan, Davut; Hunter, Jill V.; Woodbury, Suzanne L.; Raymond, Gerald; Adesina, Adekunle M.; Jhangiani, Shalini N.; Reid, Jeffrey G.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Gibbs, Richard A.; Wiszniewski, Wojciech.

In: JAMA Neurology, Vol. 70, No. 12, 2013, p. 1491-1498.

Research output: Contribution to journalArticle

Gonzaga-Jauregui, C, Lotze, T, Jamal, L, Penney, S, Campbell, IM, Pehlivan, D, Hunter, JV, Woodbury, SL, Raymond, G, Adesina, AM, Jhangiani, SN, Reid, JG, Muzny, DM, Boerwinkle, E, Lupski, JR, Gibbs, RA & Wiszniewski, W 2013, 'Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly', JAMA Neurology, vol. 70, no. 12, pp. 1491-1498. https://doi.org/10.1001/jamaneurol.2013.4598
Gonzaga-Jauregui C, Lotze T, Jamal L, Penney S, Campbell IM, Pehlivan D et al. Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA Neurology. 2013;70(12):1491-1498. https://doi.org/10.1001/jamaneurol.2013.4598
Gonzaga-Jauregui, Claudia ; Lotze, Timothy ; Jamal, Leila ; Penney, Samantha ; Campbell, Ian M. ; Pehlivan, Davut ; Hunter, Jill V. ; Woodbury, Suzanne L. ; Raymond, Gerald ; Adesina, Adekunle M. ; Jhangiani, Shalini N. ; Reid, Jeffrey G. ; Muzny, Donna M. ; Boerwinkle, Eric ; Lupski, James R. ; Gibbs, Richard A. ; Wiszniewski, Wojciech. / Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. In: JAMA Neurology. 2013 ; Vol. 70, No. 12. pp. 1491-1498.
@article{cb6ec9aaccb5449b907a517b32ce1e43,
title = "Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly",
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.",
author = "Claudia Gonzaga-Jauregui and Timothy Lotze and Leila Jamal and Samantha Penney and Campbell, {Ian M.} and Davut Pehlivan and Hunter, {Jill V.} and Woodbury, {Suzanne L.} and Gerald Raymond and Adesina, {Adekunle M.} and Jhangiani, {Shalini N.} and Reid, {Jeffrey G.} and Muzny, {Donna M.} and Eric Boerwinkle and Lupski, {James R.} and Gibbs, {Richard A.} and Wojciech Wiszniewski",
year = "2013",
doi = "10.1001/jamaneurol.2013.4598",
language = "English (US)",
volume = "70",
pages = "1491--1498",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "12",

}

TY - JOUR

T1 - Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly

AU - Gonzaga-Jauregui, Claudia

AU - Lotze, Timothy

AU - Jamal, Leila

AU - Penney, Samantha

AU - Campbell, Ian M.

AU - Pehlivan, Davut

AU - Hunter, Jill V.

AU - Woodbury, Suzanne L.

AU - Raymond, Gerald

AU - Adesina, Adekunle M.

AU - Jhangiani, Shalini N.

AU - Reid, Jeffrey G.

AU - Muzny, Donna M.

AU - Boerwinkle, Eric

AU - Lupski, James R.

AU - Gibbs, Richard A.

AU - Wiszniewski, Wojciech

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84890424575&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890424575&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2013.4598

DO - 10.1001/jamaneurol.2013.4598

M3 - Article

VL - 70

SP - 1491

EP - 1498

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 12

ER -