Identification of New Causative Genetic Mutations of Familial Early Onset Parkinsonism in Iranian Population Using Next Generation Sequencing Technique (NGS)

Parkinsonism is a chronic disorder with considerable burden worldwide. This neurogenetic disease is the most common movement disorder and the second most common neurodegenerative disorder after Alzheimer disease. The approximate prevalence of Parkinsonism is reported to be 572 per 100,000 individual older than 45 years of age. The cardinal manifestations include muscle rigidity, bradykinesia, postural instability, and resting tremor. Parkinsonism’s manifestations occur before the age of 50 in about 10% of patients. Genetic causes play a major role in Parkinson and account for up to 15% of cases. Moreover, most of the hereditary forms of Parkinson categorized in theearly-onset group. However, most of the genetic causes are still unknown. So, finding the genetic basis of earlyonset Parkinsonism will be helpful in determining the true nature of this disorder and providing new insights for further therapies in the near future. Material andMethods: Forty-one familial early-onset Parkinson patients who were referred to the genetic clinic of Ghaem hospital were enrolled in the present study. After taking a brief history and performing a complete neurologic physical examination by a neurologist, the patient’s pedigree drowns by a geneticist. Only the patients who had at least 2 family members with Parkinsonism will be included and those patients witha history of head trauma or using any medication were not included. Whole exome sequencing with the depth of 150X will be performed for each patient and homozygosis mapping will be performed for each family. Then, the putative variants will be confirmed by Sanger sequencing and segregation analysis. Results: In the six families that have been studied so far, we found two completely pathogen mutations in the known genes of this disease (PARK2 & PINK1). There are also several variants of unknown significance (VUS) that have a strong correlation with patient phenotypes. In one of our families, we found a mutation in a new possible causative gene that has not been reported in studies.All mutations were confirmed by analysis in families.Conclusion: Better understanding the etiology of this disease helps to better diagnose and treat it. Due to the high rate of consanguineous marriage in Iran, there are many undiscovered recessive genes that make it difficultto genetic cause’s diagnosis. genetic causes of a high proportion of Iranian families are not recognized by present genetic panels. The aim of this study is to make patients’ genetic recognition panels more complete and to find new therapeutic targets.