Genetic overlap between dystonia and other neurologic disorders: A study of 1, 100 exomes. (September 2022) - Dzinovic, Ivana
Abstract: Introduction: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia. Methods: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability. Results: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia. Conclusions: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations. Highlights: 1100 dystonia exomes were studied to identify genetic overlap with other neurologic disorders. 80% of 220 diagnosed presentations were related to genes found in non-dystonia gene panels. Strongest overlap was seen for genes associated with intellectual disability, epilepsy, ataxia, and HSP. 71% of identified genes were found in non-dystonia panels but not in an expert-curated gene list for dystonia.