Untersuchung des monogenen essentiellen Tremors durch Exom-Sequenzierung
Humangenetik
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Essential tremor (ET) commonly runs in families in a pattern compatible with autosomal dominant inheritance. All attempts to identify causative genes using single-family positional cloning strategies failed until today. We assume that the main reason could be phenocopies by a strong bias towards diagnosing tremor in a family with an index patient with ET. We hypothesized that this problem could be overcome by exome-sequencing a large number of index-cases from families with presumably autosomal dominant ET and looking for genes harboring potentially pathogenic variants in a number of families. This approach assumes a major effect gene that is causative in a significant proportion of all families. We estimate that our collection of 115 families should permit a gene causing ET in 10% to 20% of all families. We analyzed exome sequences of 225 exomes in these 115 families using this approach as well as the traditional single-family approach. Despite good exome sequencing quality, we did not identify a single high-confidence causative gene. We name three possible reasons for this failure: (1) Monogenic ET does not exist or is extremely rare. (2) Monogenic ET shows an extremely high locus-heterogeneity and it might be necessary to analyze an even larger family collection. (3) Exome sequencing cannot find the mutation types causing monogenic ET, e.g. intermediate to large duplications/deletions, intronic mutations or repeat expansions. We will perform high-resolution whole-genome genotyping (Illumina GSAv3) in the near future to perform a thorough analysis of genomic rearrangements. We conclude that novel, objective methods to diagnose tremor diseases with high certainty and evidence that at least ET subgroups have a common biological basis are needed before performing further family studies. However, we acknowledge that larger scale exome- or genome-sequencing projects might still unravel genes causing monogenic ET and will try to contribute to such studies with our data.
