Role of ANO3 mutations in dystonia: A large-scale mutational screening study
Newly suggested gene-disease associations need confirmatory follow-up by large-scale epidemiological studies; CENTOGENE actively engages in pertinent research projects. A recent example addressed the hypothetical link between ANO3 and movement disorders. Screening of >1,000 patients revealed strong support of a pathogenic role for heterozygous ANO3 missense variants in Parkinson’s disease and dystonia. The findings were published in Parkinsonism & Related Disorders ahead of print recently.
Parkinsonism Relat Disord. 2019 Jan 2. pii: S1353-8020(18)30564-9. doi: 10.1016/j.parkreldis.2018.12.030. [Epub ahead of print]
The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls.
To screen >1000 patients with movement disorders for rare ANO3 variants.
We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis.
Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation.
This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.