Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F17%3A10365702" target="_blank" >RIV/00064165:_____/17:10365702 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/17:10365702

Result on the web

<a href="http://dx.doi.org/10.1007/s10048-017-0521-9" target="_blank" >http://dx.doi.org/10.1007/s10048-017-0521-9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s10048-017-0521-9" target="_blank" >10.1007/s10048-017-0521-9</a>

Result language

angličtina

Original language name

Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing

Original language description

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&apos;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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/GA16-13323S" target="_blank" >GA16-13323S: MIcro and MAcro Connectomics of the Subthalamic nucleus in humans: impact of neuromodulation and dopamine depletion</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Neurogenetics

ISSN

1364-6745

e-ISSN

—

Volume of the periodical

18

Issue of the periodical within the volume

4

Country of publishing house

DE - GERMANY

Number of pages

11

Pages from-to

195-205

UT code for WoS article

000416416000003

EID of the result in the Scopus database

2-s2.0-85028567605