👤 Gianina Demarchi

To investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years. All consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology. Study population was investigated by ajmaline challenge and echocardiographic assessment over time. Genetic testing was performed using next-generation sequencing panel, containing 174 genes associated to inherited cardiac diseases, and Sanger sequencing confirmation of suspected variants with clinical implication. Of 2510 patients who underwent PM implantation, 15 (0.6%) were young adults (median age: 44 years, male predominance) presenting with advanced AVB of unknown origin. The average incidence of idiopathic AVB computed over the 2010-2019 time window was 0.7 per 100 000 persons per year (95% CI 0.4-1.2). Most of patients (67%) presented with specific genetic findings (pathogenic variant) or variants of uncertain significance (VUS). A pathogenic variant of PKP2 gene was found in one patient (6.7%) with no overt structural cardiac abnormalities. A VUS of TRPM4, MYBPC3, SCN5A, KCNE1, LMNA, GJA5 genes was found in other nine cases (60%). Of these, three unrelated patients (20%) presented the same heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene. Diagnostic re-assessment over time led to a diagnosis of Brugada syndrome and long-QT syndrome in two patients (13%). No cardiac events occurred during a median follow-up of 72 months. Idiopathic AVB in adults younger than 50 years is a very rare condition with an incidence of 0.7 per 100 000 persons/year. Systematic investigations, including genetic testing and ajmaline challenge, can lead to the achievement of a specific diagnosis in up to 20% of patients. Heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene was found in an additional 20% of unrelated patients, suggesting possible association of the variant with the disease. Show less

Pituitary adenomas are among the most frequent intracranial neoplasms and treatment depends on tumor subtype and clinical features. Unfortunately, non responder cases occur, then new molecular targets are needed. Notch system component expression and activation data are scarce in pituitary tumorigenesis, we therefore aimed to characterize Notch system in pituitary tumors of different histotype. In human pituitary adenomas we showed Show less

Apoproteins (also known as apolipoproteins) have been studied extensively because of their role in lipid transport, association between specific genotypes and elevated serum lipid levels, and increased risk of heart disease. There is considerable genetic variation in the geographic distributions of these markers, with a north-south cline of the APOE*4 allele observed in Europe by Lucotte et al. ([1997] Hum Biol 69:253-262). This study compares the frequencies of seven APO (APOA1 -75 bp, APOA1 +83 bp, APOB Ins/Del, APOB XbaI, APOC3 SstI, and APOE) and LPL loci in Mennonite populations from Kansas and Nebraska. In total, 277 individuals were sampled from Goessel, Meridian, Garden View, and Lone Tree in 2002-2004. In addition, DNA samples that were collected in 1981 from Henderson, Nebraska, were genotyped for the seven APO and LPL loci. Of the seven APO and LPL loci tested, only one locus, APOB XbaI, departed significantly from Hardy-Weinberg equilibrium, with an unexpected excess of observed heterozygotes. The frequencies of the several APO loci are unique among the Mennonites, separating them from other European populations. A bidimensional scaling representation of Reynold's co-ancestry distances based on allelic frequencies of the seven APO and LPL markers in five Mennonite congregations fails to represent schematically the known patterns of fission. It is unclear whether the observed patterns are due to selection operating on these loci or whether genetic drift, small populations sizes, or a lack of statistical power of these biallelic loci distort the observed genetic relationship among congregations. Show less