Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
PubMed
28849312
DOI
10.1007/s10048-017-0521-9
PII: 10.1007/s10048-017-0521-9
Knihovny.cz E-zdroje
- Klíčová slova
- Combined dystonia, Complex dystonia, Exome, Genetic heterogeneity, Mutation,
- MeSH
- adenylátcyklasy genetika MeSH
- dospělí MeSH
- dystonické poruchy diagnóza genetika MeSH
- dystonie diagnóza genetika MeSH
- exom genetika MeSH
- fenotyp MeSH
- genetické testování metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace genetika MeSH
- proteiny přenášející GABA přes plazmatickou membránu genetika MeSH
- sodíko-draslíková ATPasa genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenylátcyklasy MeSH
- adenylyl cyclase type V MeSH Prohlížeč
- ATP1A3 protein, human MeSH Prohlížeč
- proteiny přenášející GABA přes plazmatickou membránu MeSH
- SLC6A1 protein, human MeSH Prohlížeč
- sodíko-draslíková ATPasa MeSH
Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.
Department of Neurology Medical University Innsbruck Innsbruck Austria
Institut für Humangenetik Helmholtz Zentrum München Munich Germany
Institut für Humangenetik Technische Universität München Munich Germany
Zobrazit více v PubMed
Eur J Hum Genet. 2015 Mar;23(3):292-301 PubMed
J Neurol Sci. 2008 Oct 15;273(1-2):148-51 PubMed
J Neural Transm (Vienna). 2017 Apr;124(4):417-430 PubMed
Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5 PubMed
Mov Disord. 2013 Jun 15;28(7):889-98 PubMed
Cell. 1999 Dec 10;99(6):577-87 PubMed
Eur J Hum Genet. 2005 Sep;13(9):1086-93 PubMed
Science. 1995 Jun 23;268(5218):1749-53 PubMed
Am J Hum Genet. 2016 Dec 1;99(6):1377-1387 PubMed
Hum Mol Genet. 2005 Jan 15;14(2):307-18 PubMed
Nat Genet. 2017 Feb;49(2):223-237 PubMed
Mov Disord. 2017 Apr;32(4):569-575 PubMed
Neurology. 2009 Aug 4;73(5):400-1 PubMed
Am J Hum Genet. 2006 Jun;78(6):947-60 PubMed
Hum Mutat. 2009 Nov;30(11):1551-7 PubMed
Mov Disord. 2017 Apr;32(4):549-559 PubMed
Curr Neurol Neurosci Rep. 2017 Mar;17 (3):26 PubMed
Mov Disord. 2010 Aug 15;25(11):1538-49 PubMed
Genome Res. 2015 Mar;25(3):305-15 PubMed
Mov Disord. 2009 Feb 15;24(3):465-6 PubMed
Neurology. 2015 Mar 10;84(10):1053-9 PubMed
Hum Mutat. 2015 Jun;36(6):648-55 PubMed
Genet Med. 2012 Aug;14(8):759-61 PubMed
Pediatr Neurol. 2016 Nov;64:77-79 PubMed
Science. 2004 May 21;304(5674):1158-60 PubMed
J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1239-44 PubMed
Eur J Paediatr Neurol. 2017 Mar;21(2):245-246 PubMed
Mov Disord. 2016 May;31(5):607-9 PubMed
Nat Methods. 2010 Apr;7(4):248-9 PubMed
Front Neurol. 2017 Jan 30;8:9 PubMed
Hum Mol Genet. 2004 Sep 15;13(18):2155-63 PubMed
Hum Mutat. 2012 Oct;33(10):1408-22 PubMed
Neurology. 2012 Feb 28;78(9):649-57 PubMed
Genet Med. 2015 May;17(5):405-24 PubMed
J Neurol Neurosurg Psychiatry. 2015 Jul;86(7):774-81 PubMed
Mov Disord. 2013 Jun 15;28(7):863-73 PubMed
Nat Genet. 2014 Mar;46(3):310-5 PubMed
Mov Disord. 2017 Jan;32(1):162-165 PubMed
Cerebellum. 2009 Mar;8(1):22-7 PubMed
Neurology. 2015 Dec 8;85(23 ):2026-35 PubMed
Mov Disord. 2016 Apr;31(4):436-57 PubMed
Neurology. 2013 Sep 24;81(13):1148-51 PubMed
J Neurol Sci. 2014 Feb 15;337(1-2):219-23 PubMed
Nat Genet. 2001 Sep;29(1):66-9 PubMed
J Med Genet. 2017 Mar;54(3):155-156 PubMed
Am J Hum Genet. 2015 May 7;96(5):808-15 PubMed
Eur J Hum Genet. 2017 Feb;25(2):176-182 PubMed
