Identification of candidate genes for familial essential tremor

Essential tremor (ET) is one of the most common movement disorders in humans and is characterized by action tremors that occur during voluntary motion. However, due to the strong heterogeneity exhibited by ET patients at etiological, clinical and pathological levels, the genetic architecture and pathophysiology of the disease remain largely unknown. In this thesis, whole exome sequencing and pedigree analysis were performed in 3 ET families with histories consistent with an autosomal dominant pattern of inheritance. In two independent families, we observed a rare variant that cosegregated with the disease and was predicted to affect the function of the protein. In one of these families, a homozygous variant was identified in one affected patient and a heterozygous variant was determined in five affected family members. In a second, four-generation Turkish family, the same heterozygous variant was identified in three ET cases while remaining absent in unaffected family members. In addition, whole exome sequencing allowed us to demonstrate that other missense mutation segregate with essential tremor in a different consanguineous Turkish family. Both variants were observed to involve amino acid substitutions of highly conserved domains. Furthermore, both of the affected genes are expressed in the brain and function as regulatory elements of the central nervous system. Consequently, we propose that these variants are risk factors involved in the etiology of hereditary ET, and suggest that whole exome sequencing can serve as an effective means of identifying other alleles associated with the disease.