Objective: To gain a better understanding of the genetic basis of familial tremor syndromes.

Background: The genetic basis of tremor is poorly understood and familial tremor syndromes may be due to Parkinson’s disease (PD), essential tremor (ET), dystonic tremor (DT) or a combination of these phenotypes at an individual or family-wide level. Classification is often limited by reported clinical features in previous generations, who had not received a formal neurological diagnosis.  Possible genetic diagnoses include familial tremor dominant PD (e.g. PARK2 and LRRK2), primary dystonia (e.g. ANO3) and ataxia/tremor syndromes (e.g. SCA-12 and FXTAS). However, it is likely that novel pathogenic genetic variants are yet to be described.

Method: We have recruited a series of individuals and families across the United Kingdom with early onset (<45 years) or familial (3 or more affected family members) tremor syndromes. They have been classified according to available clinical information and are being genotyped with the Neurobooster array (NBA) and whole genome sequencing (WGS) as part of the GP2 program.

Results: We have recruited 145 families divided into: families with history of ET or DT (Group 1, N =  47), families consisting of tremor or PD cases with family history of both PD and tremor (Group 2, N = 32), families with early onset ET/DT (Group 3, N = 23) and cases with prodromal ET/DT leading to a later diagnosis of PD (Group 4, N = 43). We have enrolled 97 individuals with ET/DT from 69 families to the study, with an average number of 3.94 total affected family members including those with PD and tremor. The average age of onset of a tremor syndrome was 30.27 years, and the average interval between tremor onset and PD onset was 3.69 years. Genotyping of affected family members has not identified pathogenic mutations in known dystonia or PD genes. Further analysis is ongoing.

Conclusion: Familial forms of tremor are common and most familial tremor cases do not carry mutations in known dystonia or PD genes. Further analysis of segregating genetic variants is underway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-uk-kindreds-with-familial-tremor-in-the-global-parkinsons-genetics-progam-gp2/