Objective: To identify potentially pathogenic genomic variations associated with dystonia phenotypes in Asian Indian patients with dystonia.

Background: The Asian Indian population is underrepresented in genetic studies of dystonia and the pathogenic variations associated with dystonia in this population remain largely unknown.

Method: The Indian Movement Disorder Registry and Biobank is a multi-centric clinical registry and DNA biorepository for Indian patients with suspected genetic movement disorders. As part of this registry, our center enrolled 550 probands and affected/unaffected family members with dystonia from Sep 2018- Sep 2021. Standardized videotaped clinical examination, family history and relevant investigations were captured and stored on a REDCap platform. We performed whole exome sequencing (WES) of DNA specimens obtained from 137 probands with isolated, combined or complex dystonia in this cohort. DNA libraries were sequenced to depths of 80-100X on an Illumina platform. We followed the GATK best practices framework for variant calling and prioritized variants according to prespecified criteria. Finally, variants were classified according to ACMG guidelines.

Results: The mean age of the WES cohort was 34.7±15.9 years and age at onset was 27.2±15.5 years. Dystonia was early onset in 43.8% and generalized in 17.5%. Family history was positive for dystonia or another movement disorder in 73%. 76% had isolated dystonia, 11% combined and 13% were complex phenotypes. WES identified pathogenic/ likely pathogenic variants in 25 patients (18.2%) including 8 novel variants in known dystonia genes. Mutations in THAP1 were most common followed by SCGE, VPS16, PANK2, GLB1, FTL, TOR1A, TUBB4A, ATP13A2, ANO3, TH, FBN1, RTN2 and COQ8A.Variants of uncertain significance were identified in additional 59 participants- most commonly in the COL6A3 gene.

Conclusion: WES identified potentially pathogenic variations in 18.2% patients in this cohort. Several genes known to be associated with dystonia were replicated in this cohort of Indian dystonia, with novel variants in some. This is the largest cohort of genetically defined dystonia in the Asian Indian population. Ethnicity specific genetic information from underrepresented populations may help to further identify novel genes/variants and address the missing heritability in rare disorders.

« Back to 2022 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-landscape-of-dystonia-in-asian-indian-patients/