SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey.

SYNE1 related autosomal recessive cerebellar ataxia type 1 (ARCA1) is a late-onset cerebellar ataxia with slow progression originally demonstrated in French-Canadian populations of Quebec, Canada. Nevertheless, recent studies on SYNE1 ataxia have conveyed the condition from a geographically limited pure cerebellar recessive ataxia to a complex multisystem phenotype that is relatively common on the global scale. To determine the underlying genetic cause of the ataxia phenotype in a consanguineous family from Turkey presenting with very slow progressive cerebellar symptoms including dysarthria, dysmetria, and gait ataxia, we performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in two affected siblings. We identified a homozygous variant in SYNE1 (NM_033071.3: c.13086delC; p.His4362GlnfsX2) in all four affected siblings. This variant presented herein has originally been associated with only pure ataxia in a single case. We thus present segregation and phenotypic manifestations of this variant in four affected family members and further extend the pure ataxia phenotype with upper motor neuron involvement and peripheral neuropathy. Our findings in turn established a precise molecular diagnosis in this family, demonstrating the use of WES combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.

Identifying SNP targeted pathways in partial epilepsies with genome-wide association study data.

PURPOSE: In a recent genome-wide association study for partial epilepsies in the European population, a common genetic variation has been reported to affect partial epilepsy only modestly. However, in complex diseases such as partial epilepsy, multiple factors (e.g. single nucleotide polymorphisms, microRNAs, metabolic and epigenetic factors) may target different sets of genes in the same pathway, affecting its function and thus causing the disease development. In this regard, we hypothesize that the pathways are critical for elucidating the mechanisms underlying partial epilepsy. METHODS: Previously we had developed a novel methodology with the aim of identifying the disease-related pathways. We had combined evidence of genetic association with current knowledge of (i) biochemical pathways, (ii) protein-protein interaction networks, and (iii) the functional information of selected single nucleotide polymorphisms. In our present study, we apply this methodology to a data set on partial epilepsy, including 3445 cases and 6935 controls of European ancestry. RESULTS: We have identified 30 overrepresented pathways with corrected p-values smaller than 10(-12). These pathways include complement and coagulation cascades, cell cycle, focal adhesion, extra cellular matrix-receptor interaction, JAK-STAT signaling pathway, MAPK signaling pathway, proteasome, ribosome, calcium signaling and regulation of actin cytoskeleton pathways. Most of these pathways have growing scientific support in the literature as being associated with partial epilepsy. We also demonstrate that different factors affect distinct parts of the pathways, as shown here on complement and coagulation cascades pathway with a comparison of gene expression vs. genome-wide association study. CONCLUSIONS: Traditional studies on genome-wide association have not revealed strong associations in epilepsies, since these single nucleotide polymorphisms are not shared by most of the patients. Our results suggest that it is more effective to incorporate the functional effect of a single nucleotide polymorphism on the gene product, protein-protein interaction networks and functional enrichment tools into genome-wide association studies. These can then be used to determine leading molecular pathways, which cannot be detected through traditional analyses. We hope that this type of analysis brings the research community one step closer to unraveling the complex genetic structure of epilepsies.