Genetic Modifiers in Early-Onset Primary Dystonia

DYT1 dystonia, a hereditary movement disorder, is most often caused by a heterozygous in-frame TOR1A deletion (c.907_909delGAG) in Ashkenazi Jewish individuals. Only 30%-40% of delGAG carriers show symptoms, and disease onset typically occurs before age 26 years. The reduced penetrance is partially attributed to a genetic modifier, rs1801968. To search for additional modifiers, we compared genomic data of manifesting and non-manifesting adults. Following informed consent, all subjects were assigned a clinical disease score ranged 0-4, and genotyped for the delGAG variant. Exome sequencing was done for 45 individuals from 18 families, whole genome sequencing (WGS) for 8 individuals, and targeted sequencing of the 3`UTR of TOR1A for all individuals. Single nucleotide variants of potential interest were identified in genes encoding proteins of the lysosomal or autophagy pathways and in genes associated with neurodegenerative diseases. The overall mutation burden of nonsynonymous variants in these genes was evaluated, but was not significantly different between the groups. WGS did not identify any structural variants in the vicinity of TOR1A, but did indicate possible differences in the 3`UTR, eliciting targeted sequencing of the 3`UTR in all individuals. A haplotype represented by two SNPs (rs1182 and rs3842225) appeared more often in non-manifesting individuals, and was always inherited in trans to the delGAG variant, suggesting linkage to a possible modifier. In a single family, analysis of cDNA suggested increased expression of the delGAG over the wild-type allele. In the future, polygenic risk score analysis may provide further insight into the genetic factors modifying this disease.