Genetic overlap between dystonia and other neurologic disorders: A study of 1,100 exomes

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

“…The study cohort used for primary analysis consisted of 1100 unrelated index patients with a diverse range of dystonic phenotypes, including isolated dystonia (59%) and dystonia with other neurological features and/or extraneurological involvement; detailed demographics and clinical characteristics of the patients 0 conditions have been described elsewhere. 19,20 All subjects in the cohort had been recruited from movement disorders clinics through the practices of the investigators or by referral for dystonia genetics research from various international collaboration partners. The herein described patient II-4 from family A (A-II-4) and patient III-2 from family B (B-III-2) were part of this primary analysis cohort.…”

“…19,20 Data were annotated and filtered according to established procedures with an in-house bioinformatics pipeline, as described previously. 19,20 Variant filtering included consideration of allele frequencies in population databases, expected impact on protein, gene constraint, pathogenicity predictions, and inheritance. Variants surviving the filtering steps were manually evaluated and prioritized.…”

“…18 To date, no movement disorders have been reported with variants in EIF4A2. In this study, we mined large-scale genomic datasets of patients with dystonia 19,20 to identify two independent families with multiple affected individuals who segregated an identical unique frameshift EIF4A2 variant. We found that the variant reduced eIF4A2 protein amounts consistent with haploinsufficiency, resulting in deregulation of translation control.…”

GNAO1 Haploinsufficiency Associated with a Mild Delayed‐Onset Dystonia Phenotype

“…Motivated by the findings of Wirth and colleagues, we reassessed our in-house dystonia cohort with 1100 indexcase whole-exome sequencing data sets 4,5 for the presence of rare GNAO1 variants. In addition to a set of four de novo missense changes causing previously published complex pediatric dystonia syndromes, 4,5 we observed a heterozygous interstitial deletion at 16q12.2 (61 kb) affecting the coding exons 4-8 of GNAO1 (NM_020988.3) in 2 first-degree relatives (mother and daughter) with unresolved disease (Fig. 1).…”

“…This question the current framework about genotype-phenotype correlations in GNAO1related disorders: the hypothesis of loss-of-function variants causing epileptic encephalopathy and gain-of-function variants causing a neurodevelopmental syndrome with prominent dystonia is probably oversimplistic. 4,5 It also raises the question of the factors determining intrafamilial phenotypic variability and the differences in the clinical presentation between patients carrying loss-of-function variants. Further functional work assessing the specific impact of each mutation on the striatal cyclic adenosine monophosphate synthesis pathway, as well as neuroimaging studies of GNAO1 carriers, might lead to a better understanding of these genetic, epigenetic, and environmental factors and to the refinement of genotype-phenotype correlations.…”