Objective: Clinicogenetic analysis of 57 affected probands with SNCA multiplication, 3 unaffected carriers, and their 60 families. To use informative pedigrees to identify penetrance modifiers within the SNCA locus, neighboring regions, and known variability associated with PD and cognition.

Background: SNCA dosage has been correlated with alpha-synuclein expression levels, age of motor onset and disease severity in PD. Patients with SNCA duplications present a wide range of phenotypes, while those with triplications have an earlier presentation, accompanied by psychiatric problems and cognitive decline.

Methods: DNA samples and clinical measures of disease progression and cognitive decline were collected from 57 probands and 3 unaffected individuals carrying SNCA multiplication mutations. Further clinical evaluation, with analysis of intra- and inter-familial variance, and biospecimen collection is planned. To date, DNA has been genotyped with a 1.8 million SNP Multi-Ethnic Genotyping Array (MEGA). 5’, 3’ and intron 4 SNCA STR markers are assessed along with APOE, MAPT and GBA risk factors using TaqMan genotyping and Sanger sequencing.    

Results: Of the 60 individuals (30 male/30 female), 51 had three copies of SNCA (3C), and 9 had four copies (4C). Average age of motor symptom onset for those affected was 45.3±11.1 years (3C: 47.2±10.6, 4C: 34.5±7.9). 25 of those affected have a secondary diagnosis of dementia, with average dementia onset at 51.1±12 years (3C: 56.5±9.6, 4C: 39.6±5.5) where 50% of dementia diagnoses came within 5 years of PD diagnosis (3C: 14, 4C: 1). The average length of multiplication was 2.18±2.54Mb (range: 0.16-13.83Mb) and is not correlated with age of motor onset (r=0.21).

Conclusions: With coordinating sites in Asia, Europe, and North America (lead by Nobutaka Hattori, Alexis Brice and Matt Farrer, respectively) the SNCA Multiplication Consortium uniquely serves to: 1) screen and identify new SNCA multiplication carriers; 2) harmonize clinical phenotyping; 3) expand pedigrees and; 4) develop biomarkers for alpha-synuclein-targeted therapies (see http://www.geopd.org/projects/6).

References: 1) Kara, E., Kiely, A.P., Proukakis, C. et al. (2014). A 6.4Mb duplication of the alpha synuclein locus causing frontotemporal dementia and parkinsonism: Phenotype-genotype correlations. JAMA Neurology, 7, 1162-1171.

2) Elia, A.E., Petrucci, S., Fasano, A. et al. (2013). Alpha-synuclein gene duplication: marked intrafamilial variability in two novel pedigrees. Movement disorers, 28, 813-817

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MDS Abstracts - https://www.mdsabstracts.org/abstract/snca-multiplication-consortium-clinicogenetic-analysis-of-snca-multiplication-probands-and-families/