Penetrance and disease expression of (likely) pathogenic variants associated with inherited cardiomyopathies in the general population

Background. (Likely) pathogenic variants associated with arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. Methods. We identified (likely) pathogenic variants associated with ACM, DCM and/or HCM in 200,643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analysed early signs of disease expression. Results. We found a prevalence of 1:578, 1:251 and 1:149 for (likely) pathogenic variants associated with ACM, DCM and HCM respectively. Compared to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04;2.59], p=0.030), but similar in ACM and HCM G+ (p≥0.100). More specifically, cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (OR 3.66 [95% CI 2.24;5.81], p=4.9×10-7) and HCM G+ (OR 3.03 [95% CI 1.98;4.56], p=5.8×10-7), but comparable in ACM G+ (p=0.172). In contrast, ACM G+ had more ventricular arrhythmias (p=3.3×10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009). Conclusions. In the general population, (likely) pathogenic variants associated with ACM, DCM or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease expression in these carriers from the general population remains low. Decisions on application of cascade screening and frequency of cardiological examination should be based on multiple factors, such as the variant and disease expression.

The effect of nitrogen source and quantity on disease expression of Neonectria ditissima in apple

The effects of nitrogen on the interaction between apple trees and European canker caused by Neonectria ditissima are not well understood. Previous field and laboratory studies have shown that nitrogen affects N. ditissima disease development, germination and germ-tube growth in vitro but the type of nitrogen source has not been examined in vivo. Therefore, the aim of this study was to determine the effects of root-applied nitrogen from different sources on the development of European canker on inoculated potted trees. One-year-old ‘Royal Gala’ trees were planted in a low-nitrogen growth substrate and treated with a range of concentrations of calcium ammonium nitrate (CAN) or other nitrogen sources (Ca(NO3)2, KNO3, (NH4)2SO4, NH4NO3, urea, YaraMila™) at equivalent molar rates of nitrogen as the highest CAN treatment. Treatments were applied during the growing season (Nov to May). The control treatment received no applied nitrogen. Bud and leaf scar wounds were inoculated at leaf fall with N. ditissima conidia. Tree growth and health, disease progression and leaf nitrogen content were monitored. The rate of nitrogen application affected tree diameter and leaf nitrogen content while the nitrogen source mainly affected tree survival, powdery mildew incidence, leaf weights, leaf nitrogen and European canker symptom expression. Trees treated with (NH4)2SO4 had the lowest survival rates and highest leaf nitrogen content. Disease expression was highest with NH4NO3 and lowest with KNO3 applications. The control plants (which received no additional nitrogen), showed the least amount of both growth and disease expression. Applications of CAN, even at the lowest rate (20 g), increased disease susceptibility. Increasing rates of CAN applications did not significantly increase disease incidence. Nitrogen concentration is an important factor in the disease development of European canker of apple. Field evaluation is recommended to further validate these results.

Disease Expression and Outcomes in Black and White Adults With Hypertrophic Cardiomyopathy

Background There is limited research on hypertrophic cardiomyopathy (HCM), which is the most common inherited cardiac disorder, in diverse populations, including Black individuals. Current literature lacks comprehensive data on HCM disease expression, comorbidities, and outcomes in this historically disadvantaged group. The purpose of this study was to examine structural HCM characteristics, comorbidities, and outcomes in a Black and White cohort with HCM. Methods and Results The study was a subgroup analysis from a longitudinal, prospective study on HCM, with supplemental chart review. The sample included adults (≥18 years) with a clinical diagnosis of HCM, who self‐identified as Black/African American or White. The study sample comprised 434 individuals; 57 (13.1%) were Black, and 180 (41.5%) were women. Black patients were younger than White patients, 54.6 (13.4) versus 62.5 (14.8) years, P =0.001. Black patients were more likely to have sub‐basal and diffuse hypertrophy, 22 (38.6%) versus 56 (14.9%), P <0.001, 6 (10.5%) versus 15 (4%), P =0.017, mid‐LV obstruction, 7 (12.3%) versus 21 (5.5%), P =0.025, and cardiac fibrosis ≥15%, 10 (22.2%) versus 19 (8.8%), P =0.009, than White patients. Black patients were more likely to experience appropriate implantable cardioverter defibrillator interventions, 5 (38.5) versus 5 (6.8), P <0.001 and were more likely to have ≥2 sudden death risk factors. Comorbidities were largely similar between groups, though more Black participants had Class II obesity, 12 (21.8) versus 30 (8.1), P <0.001. Both groups had similar rates of genetic testing usage. Conclusions This study underscores the need for continued research of HCM in Black populations, including tailored approaches to diagnosis and precise evaluation of cardiac anatomy.

Impact of Strain Variation of Dichelobacter nodosus on Disease Severity and Presence in Sheep Flocks in England

AprV2 and aprB2 are variants of the apr gene of Dichelobacter nodosus, the cause of footrot in sheep. They are putative markers for severe and mild disease expression. The aim of our study was to investigate the distribution of aprV2 and aprB2 in flocks with and without footrot. Our hypotheses were that both strains are present in endemically affected flocks, with aprB2 and aprV2 associated with mild and virulent phenotypes respectively but that D. nodosus is not present in flocks without footrot. Alternatively, aprB2 persists in flocks without footrot. Despite extensive searching over 3 years only three flocks of sheep without footrot were identified. D. nodosus was not detected in these three flocks. In one further flock, only mild interdigital dermatitis was observed, and only aprB2 was detected. Twenty-four flocks with endemic footrot of all severities were sampled on three occasions and all were positive for D. nodosus and the aprV2 variant; aprB2 was detected in only 11 of these flocks. AprB2 was detected as a co-infection with aprV2 in the 22% of samples positive for aprB2 and was more likely in mild footrot phenotypes than severe. Dichelobacter nodosus serogroups were not associated with footrot phenotype. We conclude that D. nodosus, even aprB2 strains, do not persist in flocks in the absence of footrot. Our results support the hypothesis that aprB2 is associated with mild footrot phenotypes. Finally, we conclude that given the small number of flocks without footrot that were identified, footrot is highly endemic in English sheep flocks.

Impact of Rootstock and Season on Red Blotch Disease Expression in Cabernet Sauvignon (V. vinifera)

Grapevine red blotch virus (GRBV), the causative agent of grapevine red blotch disease, is widespread across the United States and causes a delay in ripening events in grapes. This study evaluates the effects of GRBV on Cabernet Sauvignon grape berry composition, grafted on two different rootstocks (110R and 420A) in two seasons (2016 and 2017). Total soluble solids, acidity, and anthocyanin concentrations were monitored through ripening and at harvest. Phenolic and volatile compounds were also analyzed at harvest to determine genotypic and environmental influences on disease outcome. Sugar accumulation through ripening was lower in diseased fruit (RB (+)) than healthy fruit across rootstock and season. GRBV impact was larger in 2016 than 2017, indicating a seasonal effect on disease expression. In general, anthocyanin levels and volatile compound accumulation was lower in RB (+) fruit than healthy fruit. Total phenolic composition and tannin content was higher in RB (+) fruit than healthy fruit in only 110R rootstock. Overall, GRBV impacted Cabernet Sauvignon grape composition crafted on rootstock 110R more than those crafted on rootstock 420A.

CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC

Background Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5’ and 3’ ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. Methods In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. Results Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. Conclusions This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

The role of soil types on the relation between individual soil properties and Fusarium wilt expression in 'Gros Michel' bananas

Aims This study looks whether the response of soil management (liming and nitrogen fertilization) on the incidence of Fusarium wilt (Foc Race 1) in Gros Michel banana (Musa AAA) is influenced by soil types. Methods The effect of inoculation with Foc Race 1 was studied in a factorial greenhouse trial with eight representative soil types of the Costa Rican banana region, two pH levels; and three levels of N-fertilization. After an 8-week period, plant biomass, leaf area, and a disease index were measured.Results There were significant effects of soil pH and N, and their interactions on disease expression. Low pH levels and high N-fertilization increased the disease expression. The response to changes in soil pH and N-fertilization differed considerably between the different soil types. Conclusions Although soil pH and N influence Fusarium wilt in banana, each soil type differs in its response to these soil properties. This complicates the development of standard soil management strategies in terms of e.g., N-fertilization and liming to mitigate or fight the disease.