Parkinson's Disease via the SNCA Gene

SNCA-related Parkinson disease is a rare but important genetic cause for both familial and sporadic Parkinson disease. SNCA-related Parkinson disease 1 is known to be caused by point pathogenic variants (non copy number variants). Symptoms include slowly progressive Parkinsonism, masked face, bradykinesia, rigidity, resting tremor and gait disturbances with onset at mid to late adulthood. Patients also present with cognitive decline, depression or dementia. Patients have favorable response to Levodopa therapy (Klein and Schlossmacher 2007; Puschmann 2013).

SNCA-related Parkinson disease 4, which is known to be caused by a heterozygous triplication of the SNCA gene, is associated with the occurrence of early onset Parkinson disease with rapid progression of the disease, often with dementia and disorders of the autonomic nervous system. Compared to heterozygous triplication of SNCA, Parkinson disease caused by a heterozygous duplication of the SNCA gene shows a milder phenotype with variable penetration as low as 33% and has a good response to Levodopa therapy (Klein and Schlossmacher 2007; Oczkowska et al. 2013; Puschmann 2013).

SNCA-related Parkinson disease is inherited in autosomal dominant manner and is caused by pathogenic variants in the SNCA gene. SCNA encodes α synuclein, which is highly expressed in neurons and concentrated in their presynaptic termini and may play a role in vesicular transport processes. It has been proposed that Parkinson disease is caused by either the defective degradation of mutant α synuclein or accumulation of highly expressed α synuclein. This could explain why in Parkinson disease, α-synuclein is aggregated in Lewy body and Lewy neurites, which is the pathologic hallmark of Parkinson disease (Abeliovich and Gitler 2016; Haenseler et al. 2017).

Pathogenic variants in SNCA include missense, regulatory variants and large duplications/triplications (three copies/four copies) in the SNCA locus (Human Gene Mutation Database). One of the mechanisms for pathogenesis in SNCA-related Parkinson disease is dosage-dependent toxicity. The more copy numbers of SNCA in a patient, the more severe the disease. The breakpoint of SNCA multiplications is different in each patient, therefore, the region of duplication/triplication varies from 41.2 Mb to 0.2 Mb (La Cognata et al. 2017). De novo pathogenic variants in the SNCA gene may occur.

SNCA point pathogenic variants are a rare cause of Parkinson disease (Puschmann 2013).

Duplication or triplication of SNCA is rare, but slightly more common than point pathogenic variants. (Puschmann 2013).

This test provides full coverage of all coding exons of the SNCA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).