title: Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot-Marie-Tooth neuropathy and a mutation in HSPB1.
abstract: Charcot-Marie-Tooth disease (CMT) is a group of hereditary peripheral neuropathies. The dominantly inherited axonal CMT2 displays striking genetic heterogeneity, with 17 presently known disease genes. The large number of candidate genes, combined with lack of genotype-phenotype correlations, has made genetic diagnosis in CMT2 time-consuming and costly. In Finland, 25% of dominant CMT2 is explained by either a GDAP1 founder mutation or private MFN2 mutations but the rest of the families have remained without molecular diagnosis. Whole-exome and genome sequencing are powerful techniques to find disease mutations for CMT patients but they require large amounts of sequencing to confidently exclude heterozygous variants in all candidate genes, and they generate a vast amount of irrelevant data for diagnostic needs. Here we tested a targeted next-generation sequencing approach to screen the CMT2 genes. In total, 15 unrelated patients from dominant CMT2 families from Finland, in whom MFN2 and GDAP1 mutations had been excluded, participated in the study. The targeted approach produced sufficient sequence coverage for 95% of the 309 targeted exons, the rest we excluded by Sanger sequencing. Unexpectedly, the screen revealed a disease mutation only in one family, in the HSPB1 gene. Thus, new disease genes underlie CMT2 in the remaining families, indicating further genetic heterogeneity. We conclude that targeted next-generation sequencing is an efficient tool for genetic screening in CMT2 that also aids in the selection of patients for genome-wide approaches.
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Emil
authors: E
authors: Ylikallio
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Mridul
authors: M
authors: Johari
authors: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Svetlana
authors: S
authors: Konovalova
authors: Department of Clinical Genetics, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors: Jukka S
authors: JS
authors: Moilanen
authors: Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors: Sari
authors: S
authors: Kiuru-Enari
authors: 1] Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland [2] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors: Mari
authors: M
authors: Auranen
authors: Department of Clinical Genetics, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors: Leila
authors: L
authors: Pajunen
authors: 1] Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland [2] Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Henna
authors: H
authors: Tyynismaa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001369:Axons; D018797:Cell Cycle Proteins / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005091:Exons; D005260:Female; D005387:Finland; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C470309:MAD2L1BP protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins
references: BMC Med Genet. 2006 Jun 08;7:53
references: 16762064
references: Curr Neurol Neurosci Rep. 2011 Feb;11(1):78-88
references: 21080241
references: Ann Neurol. 2012 Jan;71(1):26-39
references: 21698661
references: N Engl J Med. 2010 Apr 1;362(13):1181-91
references: 20220177
references: J Neurodegener Dis. 2013;2013:495873
references: 26316991
references: Am J Hum Genet. 2011 Aug 12;89(2):308-12
references: 21820100
references: Hum Mutat. 2012 Nov;33(11):1610-5
references: 22730194
references: Curr Opin Neurol. 2011 Oct;24(5):475-83
references: 21892080
references: BMC Med Genet. 2010 Mar 29;11:48
references: 20350294
references: Eur J Neurol. 2011 Jan;18(1):39-48
references: 20482598
references: Cell. 1991 Jul 26;66(2):219-32
references: 1677316
references: Bioinformatics. 2011 Oct 1;27(19):2648-54
references: 21828086
references: J Cell Sci. 2009 Nov 1;122(Pt 21):3823-30
references: 19889967
references: Eur J Hum Genet. 2009 Jun;17(6):703-10
references: 19277060
references: Ann Neurol. 2011 Jan;69(1):22-33
references: 21280073
references: Genome Biol. 2011 Sep 28;12(9):R94
references: 21955854
references: Mol Pain. 2011 Dec 02;7:92
references: 22136189
references: Ann Neurol. 2013 Jan;73(1):140-5
references: 23280954
references: Neurogenetics. 2013 May;14(2):123-32
references: 23456260
references: Nat Genet. 2004 Jun;36(6):602-6
references: 15122254