Browsing by Subject "mutation"

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands’ siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. CONCLUSIONS The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.

The main focus of this study is a Finnish family, in which four out of eight children presented with an unidentified disease causing a grave developmental disorder. A genetic cause for this disorder was sought by utilizing whole exome sequencing. Both parents, two affected siblings and one healthy sibling were sequenced. After variant filtering and analysis, only the candidate gene UBA5 passed the filtering criteria. The results were validated using Sanger sequencing. Both affected individuals were shown to have compound heterozygous variants of this gene, with one of the variants being novel. No cases of disease in humans associated with UBA5 have prior to this study been reported. However, other unrelated patients with a similar phenotype have since been found to possess pathogenic variants in the gene UBA5, which confirms the claim that it's the disease-causing gene. Therefore, this study enhances our knowledge of the gene's physiological significance.

Campylobacter jejuni is one of the leading causes of human gastroenteritis. Globally, there has been an increasing trend in the incidence of campylobacteriosis. In the European Union, about 200,000 cases of campylobacteriosis are reported annually. C. jejuni 4031 was isolated from a water outbreak in Finland. This strain belongs to the ST-45 clonal complex. According to a previous study, this population has been stable over time and space and has showed low levels of genomic diversity compared with other populations. Therefore, it is meaningful to investigate the evolutionary mechanisms and ecological conditions behind these clones. The aim of this study was to investigate the evolution of C. jejuni 4031 by whole genome sequencing and bioinformatics tools, characterizing the rate and molecular spectrum of spontaneous mutation in these clones. In addition, the transformation pattern of C. jejuni 4031 was to be studied. This study composed of three independent experiments: mutation accumulation experiment, fluctuation analysis, and transformation cycle experiment, to investigate mutation and recombination events, respectively. The C. jejuni 4031 grown for 220 generations by single colony passaging method in NB2 agar plate and thereafter named C. jejuni 4031x12 was used as starting material for the studies. In total of 76 genomes from both mutation accumulation experiments and transformation cycle experiments, were subject to SNP calling. Results showed that C. jejuni 4031x12 could accumulate spontaneous mutations at a relatively low rate (4.1x10-10 mutation per generation per nucleotide) than conventional estimates, with mutational bias towards G:C>A:T transitions and coding regions. The fluctuation analysis proves that C. jejuni 4031x12 could obtain antibiotic resistance via transformation. However, no recombination events were observed from SNP results. In conclusion, C. jejuni 4031 has evolved at a much lower rate compared with prior knowledge. Results from fluctuation analysis and transformation cycle experiment suggest that there are no essential recombination barriers between C. jejuni 4031 and C. jejuni NCTC11168 but transformants may not have a competitive advantage over their non-transformed counterparts.