Objective: To identify whole exome and mitochondrial genome mutation spectrum of dystonia in India and to establish clinical significance of mutations by phenotype-genotype correlation.

Background: Dystonia is a rare movement disorder with an estimated prevalence of 16:100,000 worldwide. It is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Till date, more than 25 monogenic inherited dystonia and dystonia-related disorders (DYT1-DYT25) have been reported. Role of mitochondria have also been described in dystonia caused by errors (e.g. mutations) in the genetic material (DNA) of the mitochondria.

Method: The whole Exome Sequencing (WES) and mito exome was carried out in 65 unrelated patients and 72 healthy controls from northern part of India. All patients were clinically evaluated by the neurologist and biochemical and neuroimaging data were also collected.

Results: Among 65 patients (mean age 44 years; mean age at onset 38.5), 30 mutations were found in 37 patients (46%). KMT2B gene was identified as most common dystonia (5/37; 13.5%) gene in our study, followed by COL6A3 gene which was found in 4 dystonia patients (11%). Other identified genes are: ATP1A3 (1), ANO3 (3), AP4B1 (3), APTX (1), BAZ1B (1), DHDDS (1), DNAJC5 (1), DNMT1 (1), KCNT1 (1), KCTD17 (1), MECP2 (1), NALCN (1), PRKRA (2), SCN11A (1), SGCE (1), TAF1 (1), VPS16 (3), VPS41 (1), ZNF142 (1). All candidate variations were found absent in 72 healthy controls. We found only one mutation in mitochondrial genome (c.419T>C; p.Met140Thr; ATP6 gene).

Conclusion: The clinical phenotypes of identified mutation in our study majorly confirm to the reported phenotype of each genetic subtype (KMT2B, COL6A3 and ANO3). Genetic workup for dystonia requires extensive molecular screening of each candidate gene beyond reported mutations in HGMD

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exome-wide-and-mitogenome-sequencing-of-indian-dystonia-patients/