Objective: To report a novel SNCA likely pathogenic variant.

Background: The A53T mutation in the SNCA gene, encoding alpha-synuclein (a-syn), was the first established genetic cause of Parkinson’s disease (PD), back in 1997. Since then, a-syn has been safely established as the key culprit triggering neuronal degeneration in PD. Yet, mutations in SNCA are very rare: besides duplications and triplications of the whole gene, only six missense variants have been reported, which cause autosomal dominant PD with high penetrance. Despite clinical variability among different variants, the phenotype is usually characterized by early onset and high prevalence of non-motor signs, such as dementia, psychiatric disturbances and dysautonomia.

Method: Clinical assessment, next generation sequencing and bioinformatic modeling.

Results: We report an Italian family with a novel likely pathogenic variant in the SNCA gene. The proband, a 56-years-old woman, developed akinetorigid PD at age 47 with rapid progression, requiring sub-thalamic DBS at age 52, and dementia manifesting 6 years from onset. Two siblings, a 53-year-old male and a 57-year old female, also developed akinetorigid PD at age 50, without cognitive impairment to date. They all showed dramatic response to Levodopa and motor dyskinesias after a few years. A fourth sibling, aged 61, did not present motor signs of PD but manifested psychiatric disturbances such as depression and anxiety, at about 54 years. Neither the father, deceased at age 60, nor the mother, deceased at age 40 for cardiopathy, were reported to suffer from PD. NGS based analysis of a panel of PD-related genes revealed a novel SNCA heterozygous missense variant (p.V15A), shared by all four siblings. The variant was not present in population databases and predicted as pathogenic by all in silico tools. Bioinformatic modelling demonstrated, from an energetic point of view, a significantly reduced stability of the mutant protein compared to wild type, with formation of rather unstable intermediate structures, and with continuous alternative transitions between partially folded and unfolded conformations.

Conclusion: We report a novel SNCA likely pathogenic variant in a large family with autosomal dominant PD. The functional characterization of this variant will help shed light on the pathogenic role of a-syn in neuronal death.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-likely-pathogenic-snca-variant-associated-with-parkinsons-disease/