Whole exome sequencing of familial, combined or complex dystonia

Background: To determine the usefulness of whole exome sequencing
(WES) in the diagnostic evaluation of patients and small families with
familial, combined and/or complex forms of dystonia identified from an
adult neurology clinic at a tertiary center, and to set up a computational
pathway for the bioinformatics analyses.
Methods: By mail, we contacted all 347 patients from our department who
during a 4-year period had an ICD-10 diagnosis of dystonia. Of these, 122
were re-examined within our research study. Patients who had combined
and/or complex dystonia phenotypes and patients who reported close
family members with dystonia were examined by WES. Different
computational approaches followed (co-segregation or trio analysis,
filtering variants based on an in-house gene list with more than 500 dystonia nuclear and mitochondrial genes etc.). Copy number variants (CNVs)
were also detected by using in-silico tools.
Results: Re-examination revealed that 11 of 122 (9.0%) of patients had
other disorders. Of the remaining 111 patients, fourteen had familial, combined or complex dystonia phenotypes starting at mean 37.6 (SD 14.9)
years and were analysed by WES. For 5 of these, a definite or candidate
monogenic disease cause was identified (table).
The diagnostic yield in this project was 35,7% with positive or likely positive findings. Two of 5 patients had variants that had been described previously (40%) and the remaining 3 carried putatively pathogenic variants (60%).
Conclusions: Candidate disease-causing variants were identified in 5 out of 14 cases investigated, all these had combined or complex dystonia and relatively young onset (mean 22.3, SD 11.3 years). CNV analysis is relevant in the genetic workup of familial/combined/complex dystonia.