👤 Reet Rein

Reaching a genetic diagnosis of mitochondrial disorders (MDs) is challenging due to their broad phenotypic and genotypic heterogeneity. However, there is growing evidence that the use of whole exome sequencing (WES) for diagnosing patients with a clinical suspicion of an MD is effective (39-60%). We aimed to study the effectiveness of WES in clinical practice in Estonia, in patients with an unsolved, but suspected MD. We also show our first results of mtDNA analysis obtained from standard WES reads. Retrospective cases were selected from a database of 181 patients whose fibroblast cell cultures had been stored from 2003 to 2013. Prospective cases were selected during the period of 2014-2016 from patients referred to a clinical geneticist in whom an MD was suspected. We scored each patient according to the mitochondrial disease criteria (MDC) (Morava et al., 2006) after re-evaluation of their clinical data, and then performed WES analysis. A total of 28 patients were selected to the study group. A disease-causing variant was found in 16 patients (57%) using WES. An MD was diagnosed in four patients (14%), with variants in the The diagnostic yield of WES in our cohort was 57%, proving to be a very good effectiveness. However, MDs were found in only 14% of the patients. We suggest WES analysis as a first-tier method in clinical genetic practice for children with any multisystem, neurological, and/or neuromuscular problem, as nuclear DNA variants are more common in children with MDs; a large number of patients harbor disease-causing variants in genes other than the mitochondria-related ones, and the clinical presentation might not always point towards an MD. We have also successfully conducted analysis of mtDNA from standard WES reads, providing further evidence that this method could be routinely used in the future. Show less

The single nucleotide polymorphisms (SNPs) apolipoprotein E (APOE) epsilon3/epsilon2/epsilon4, cholesteryl ester transfer protein (CETP) TaqIB, and apolipoprotein C3 (APOC3) -482 C>T have been associated with an atherogenic lipid profile and, in some studies, with increased cardiovascular risk. However, no data exist on their combined impact on atherosclerotic disease. We therefore aimed at investigating the combined impact of these SNPs on the presence of angiographically determined coronary artery disease (CAD). Genotyping was performed in 557 consecutive Caucasian patients undergoing coronary angiography for the evaluation of CAD. From the individual SNPs, only the APOE epsilon3epsilon4/epsilon4epsilon4 genotype was significantly associated with an increased risk of significant coronary stenoses with lumen narrowing >or=50% (odds ratio (OR)=1.77 [1.16-2.71]; p=0.008). However, the risk of CAD strongly increased when more than one of the analysed genetic variants was present: ORs were 2.74 [1.29-5.83]; p=0.009 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 and the CETP B1B1 genotype, 1.97 [1.06-3.66]; p=0.031 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 genotype and the APOC3 -482T allele, 2.12 [1.31-3.44]; p=0.002 for patients with both the CETP B1B1 genotype and the APOC3 -482T allele, and 3.99 [1.57-13.79]; p=0.029 for patients with all three variants. Multivariate analyses confirmed these results. We conclude that there are strong synergistic effects of the APOE epsilon3/epsilon2/epsilon4, the CETP TaqIB, and the APOC3 -482 C>T polymorphisms on their association with CAD. Show less