Submission Details

Mutations in the SNCA gene were first reported in relation to autosomal-dominant Parkinson´s disease in 1997 (Polymeropoulos et al., PMID: 9197268). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra, and the presence of specific protein aggregates, termed Lewy bodies, in the substantia nigra and locus coeruleus. In these Lewy bodies, alpha-synuclein forms the major filamentous protein component (Spillantini et al. 1998, PMID: 9600990). Further, the mRNA expression of SNCA is increased in mid-brain tissue of sporadic patients with Parkinson´s disease (Chiba-Falek et al. 2006, PMID: 16795004). Signs and symptoms of Parkinson´s disease include tremor which is most pronounced during rest, muscle rigidity, slowing of the voluntary movements (bradykinesia), and a tendency to fall back (postural instability). Several clearly pathogenic, missense variants and SNCA gene multiplication have been reported in ~150 patients in ~50 publications (for review see Trinh et al. 2018, PMID: 30357936, www.mdsgene.org). Of these, 17 publications are included in this curation. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence of gene-disease relation for SNCA and Parkinson´s disease was reached (12 pts.). The SNCA-linked phenotype due to missense variants and gene triplications often includes cognitive decline in addition to Parkinson´s disease, has an earlier age at onset and a faster disease progression when compared to idiopathic Parkinson´s disease. In contrast, SNCA gene duplication carriers usually resemble idiopathic Parkinson´s disease. The disease follows a dominant mode of inheritance with age-dependent reduced penetrance. Penetrance seems to be the lowest for carriers of the SNCA gene duplication (Chartier-Harlin et al. 2004, PMID: 15451224, Farrer et al. 2004, PMID: 14755720). In addition to the pathogenic variants affecting the coding region of SNCA, many candidate and genome-wide association studies have identified non-coding variants within or near the SNCA locus as risk factors for Parkinson´s disease, likely through an over-expression paradigm (Nalls et al. 2019, PMID: 31701892; http://pdgene.org/view?gene=SNCA). One general mechanism of pathogenicity within Parkinson’s disease appears to be the toxic accumulation and aggregation of alpha-synuclein protein (Wong and Krainc 2017, PMID: 2817037). This gene-disease association is further supported by recurrent experimental evidence in animal models, cultured non-human cells, and patient-derived cells demonstrating a tendency for increased accumulation of mutant protein and linked mitochondrial dysfunction, which both are key findings in Parkinson´s disease (Giasson et al. 2002, PMID: 12062037; Kuo et al. 2010, PMID: 20106867; Zhou W 2000, PMID: 10825478; Li et al. 2013, PMID: 24392030; Dettmer et al. 2015, PMID: 26076669; Diao et al. 2021, PMID: 34572052). In summary, pathogenic variants in SNCA are definitively causing autosomal-dominant Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Parkinson’s Disease Gene Curation Expert Panel on April 19th, 2022.