Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
28849312
DOI
10.1007/s10048-017-0521-9
PII: 10.1007/s10048-017-0521-9
Knihovny.cz E-resources
- Keywords
- Combined dystonia, Complex dystonia, Exome, Genetic heterogeneity, Mutation,
- MeSH
- Adenylyl Cyclases genetics MeSH
- Adult MeSH
- Dystonic Disorders diagnosis genetics MeSH
- Dystonia diagnosis genetics MeSH
- Exome genetics MeSH
- Phenotype MeSH
- Genetic Testing methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation genetics MeSH
- GABA Plasma Membrane Transport Proteins genetics MeSH
- Sodium-Potassium-Exchanging ATPase genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Adenylyl Cyclases MeSH
- adenylyl cyclase type V MeSH Browser
- ATP1A3 protein, human MeSH Browser
- GABA Plasma Membrane Transport Proteins MeSH
- SLC6A1 protein, human MeSH Browser
- Sodium-Potassium-Exchanging ATPase 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
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