Research Projects

Dystonia is a rare and disabling movement disorder characterized by involuntary, sustained muscle contractions leading to abnormal postures and repetitive movements. It encompasses a genetically diverse group of conditions with more than 200 genes implicated globally. However, despite the availability of next-generation sequencing (NGS) technologies like whole-exome sequencing (WES) and whole-genome sequencing (WGS), the diagnostic yield in dystonia remains suboptimal, especially in underrepresented populations like India, where the yield is reported to be ~20%. A major contributor to this diagnostic gap is the inability of short-read sequencing (SRS) to detect structural variants (SVs), short tandem repeats (STRs), and variants in repetitive or hard-to-sequence regions. Furthermore, variants of uncertain significance (VUS), particularly in non-European populations, present a major interpretive challenge due to limited reference datasets and lack of functional validation. This project aims to systematically address these challenges and improve the diagnostic yield in Indian patients with dystonia. We propose a multi-institutional effort involving recruitment of clinically diagnosed dystonia patients from diverse Indian population and establishment of a well-annotated clinical registry and biorepository. Whole exome and whole genome sequencing will be performed as a first-tier approach to identify pathogenic or likely pathogenic variants. For patients who remain undiagnosed after WES/WGS, long-read sequencing (LRS) technologies such as Oxford Nanopore will be applied. LRS offers the advantage of detecting complex SVs, STRs, and deep intronic or repetitive region variants missed by SRS. In addition, LRS also helps detect epimutations, imprinting disorders, or mosaic methylation patterns relevant in rare syndromes (e.g. histone lysine methyltransferase (KMT2B)-deficient dystonia). The expected outcomes of the project include increased early and accurate diagnostic yield for dystonia in the Indian population. The multi-tiered approach will lead to identification of novel pathogenic variants and genes and improve the interpretation and reclassification of VUS. This study will not only enhance our understanding of the genetic architecture of dystonia in India but also pave the way for precision diagnostics, informed clinical management, and future therapeutic interventions.