TY - JOUR
T1 - Molecular diversity of combined and complex dystonia
T2 - insights from diagnostic exome sequencing
AU - Zech, Michael
AU - Jech, Robert
AU - Wagner, Matias
AU - Mantel, Tobias
AU - Boesch, Sylvia
AU - Nocker, Michael
AU - Jochim, Angela
AU - Berutti, Riccardo
AU - Havránková, Petra
AU - Fečíková, Anna
AU - Kemlink, David
AU - Roth, Jan
AU - Strom, Tim M.
AU - Poewe, Werner
AU - Růžička, Evžen
AU - Haslinger, Bernhard
AU - Winkelmann, Juliane
N1 - Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - Combined dystonia
KW - Complex dystonia
KW - Exome
KW - Genetic heterogeneity
KW - Mutation
UR - http://www.scopus.com/inward/record.url?scp=85028567605&partnerID=8YFLogxK
U2 - 10.1007/s10048-017-0521-9
DO - 10.1007/s10048-017-0521-9
M3 - Article
C2 - 28849312
AN - SCOPUS:85028567605
SN - 1364-6745
VL - 18
SP - 195
EP - 205
JO - Neurogenetics
JF - Neurogenetics
IS - 4
ER -