Objective: To identify the genetic cause of early-onset Parkinson’s disease (EOPD) in a Serbian family.

Background: Hereditary EOPD is a genetically heterogeneous neurodegenerative disorder, characterized by an early onset (<50 years) and frequently an autosomal recessive mode of inheritance. We have identified a small family from Serbia with three female members in two generations (two sisters and a daughter/niece) affected by EOPD, thus likely consistent with an autosomal dominant inheritance. The ages of onset were 35, 25, and 17 years, respectively. In addition to the motor phenotype all three patients exhibited cognitive impairment and behavioral changes.

Methods: Exome sequencing was performed on the aunt-niece pair and on an unaffected uncle. The resulting variant calls were annotated in house using Annovar. Filtering steps included exclusion of non-rare variants, i.e., minor allele frequency (MAF) > 0.01 and exclusion of variants in non-conserved regions. Heterozygous non-synonymous, frameshift, or truncating variants that were shared by the affected individuals and not present in the unaffected family member were extracted.

Results: The filtering steps that we applied resulted in 17 candidate changes in genes expressed in the brain. Among these, we identified a missense mutation (p.Pro359Leu) in the TGM6 gene as the most plausible candidate. This particular change was found only nine times among the >60,000 exomes in the ExAC database. TGM6 encodes Transglutaminase 6 and to date five missense mutations in this protein have been described to cause spinocerebellar ataxia type 35 (SCA35). Interestingly, the mutation we found has a very high CADD score of 34 (range of CADD scores for missense mutations: 0-39, significance cut-off: 15).

Conclusions: We have identified a missense mutation in the TGM6 gene as the likely disease-causing variant in a small family affected with autosomal dominant EOPD. Missense mutations in this gene have been related to another movement disorder, i.e. SCA35, although the change we identified has a CADD score higher then the ones previously reported (range: 16-29). Importantly, various types of SCA have been shown to clinically overlap with PD. Nevertheless, given the limited size of the family we investigated, no meaningful segregation analysis could be performed. Thus, mutational screening of TGM6 in other familial EOPD cases is warranted in order to further explore the role of this gene in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/do-mutations-in-the-tgm6-sca35-gene-cause-early-onset-parkinsons-disease/