Genetic Sketch of Parkinson's Disease in India.

abstractBy the current estimates, India is likely to face an alarmingly high burden of Parkinson's disease (PD) in the next two decades. Untangling the pathophysiology of PD through genetic research is the key to precision medicine and prevention strategies. This narrative review serves dual purpose of recapitulating phenomenology of monogenic diseases presenting with parkinsonism and synthesizing knowledge on PD genetics gained through research in India over the past two decades. Recent studies have detected rare genetic variants in 15%-20% of the early-onset PD patients in India. Due to lack of segregation analysis and functional validation, a vast majority of these remain as variants of uncertain significance. Nevertheless, several potentially pathogenic variants detected in the Indian PD patients are not yet cited in the global genetic databases such as Movement Disorder Society Genetic mutation database. Biallelic mutations (pathogenic single-nucleotide variants and copy number variants) in the PRKN gene account for 3%-5% of monogenic early-onset PD in the Indian population. About 2%-3% of the Indian EOPD patients carry pathogenic variants in the genes associated with atypical parkinsonism, such as PLA2G6 , suggesting that initially, they may be indistinguishable from monogenic PD. Up to 10% of the PD patients in India carry heterozygous pathogenic variants in GBA1 , a risk factor gene. Genetic research in India has several critical gaps, such as uneven geographic or ethnic representation, discrepancies in variant classification, and lack of large-scale genome-wide association studies. Sustained nationwide as well as international collaborative efforts are needed to bridge these gaps and foster translational science.