Objective: To identify copy number variants (CNVs) associated with isolated or combined dystonia in Indian patients using chromosomal microarray analysis (CMA).

Background: Chromosomal aberrations, especially CNVs including microduplications and microdeletions, that are beyond the resolution of standard G-band karyotyping or next generation sequencing may account for the missing heritability in a subset of patients with genetic dystonia. This study assessed genomic microstructural alterations in Indian patients with dystonia, using CMA.

Method: We obtained DNA specimens from participants with dystonia enrolled in the Indian Movement Disorders Registry and Biobank. We collected clinical data including demographic details, phenotypic information and medication log, along with a structured video protocol. CMA was performed in 68 subjects using an Affymetrix CytoScan™ 750k array. Data was analyzed using Chromosome Analysis Suite (ChAS) version 4.2.1. To detect CNVs, we filtered the data for  ≥200kb gains/losses and ≥25 marker counts. CNVs and region of homozygosity (ROH) were classified according to ACMG guidelines.

Results: The mean age of the cohort was 30.7 ± 14.6 years, age at onset was 21.5 ± 15.7 years and duration of symptoms was 9.2 ± 7.9 years. Dystonia was early onset in 52.9% and generalized in 29.4%. Family history was positive for dystonia or another movement disorder in 45.6%. 55.9% had isolated dystonia, 14.7% combined and 19.1% were complex phenotypes. CMA identified 19 pathogenic/likely pathogenic variants in 12 patients including 8 gains and 4 losses. Potentially pathogenic variations were most frequent in Chromosome 1. Chromosomal mosaicism was present in 7 cases. The DYT13 locus was the most frequently identified variation, followed by chromosome 16p13.3 deletion and CNVs in DYT17, DYT21, TAF1, PARK2 and PEX10. Additionally, variants of uncertain significance were identified in 35 patients, CNVs in 28 patients and ROH in 7 patients respectively, with the most common abnormalities in chromosome X and 11.

Conclusion: CMA could detect potentially pathogenic copy number variants in 17.7% of patients with dystonia. Our results point towards the utility of CMA as an adjunct investigation in suspected genetic dystonia, including the adult onset dystonia population. Inability to identify individual genes, specifically within genomic regions susceptible to CNVs remains a limitation of this technique.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chromosomal-microarray-analysis-for-genetic-evaluation-of-dystonia/