Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes:The Importance of Functional Studies above Prediction

Genetic variants in gene-encoding proteins involved in cell-cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype-phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype-phenotype correlations, we separate variants into 'protein reducing' or 'altered protein' variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

At the intersection of cultural and natural heritage: Distribution and conservation of the type localities of Italian endemic vascular plants

We conducted a GIS spatial analysis with the aim of providing the first quantitative large-scale overview of the distribution patterns of 1536 type localities (loci classici) of 1216 Italian endemic vascular plants and their relationship with a set of descriptive variables. Whereas some variables were used to model the presence-absence distribution patterns of the type localities for the whole set of endemics as well as for the subset of narrow endemics, others (e.g., presence inside or outside protected areas and Italian Important Plant Areas) were considered with the purpose of assessing potential assets or risks for conservation. The largest number of type localities was found within the Mediterranean biogeographic region (1134), followed by the Alpine region (306) and Continental region (96). A total of 670 locations are located on islands, whereas 866 are located on the Italian mainland (139 and 124 in the case of narrow endemics, respectively). A large number of type localities are located in mountainous areas and along the coastline, which can be seen as a potential risk for conservation. On the contrary, we detected a positive correlation with the distance from roads, which might be considered to be an asset. Importantly, 1030 type localities fall inside protected areas, whereas 506 localities fall outside protected areas, with 259 of these unprotected localities on islands. We propose considering the results of the analysis of the distribution of type localities of Italian endemics to be a strategic tool for conservation planning and resource management. Application of plant micro-reserves and integration of diverse legislation tools are suggested to strengthen efforts and increase conservation success

Specialist laboratory networks as preparedness and response tool - The emerging viral diseases-expert laboratory network and the chikungunya outbreak, Thailand, 2019

We illustrate the potential for specialist laboratory networks to be used as preparedness and response tool through rapid collection and sharing of data. Here, the Emerging Viral Diseases-Expert Laboratory Network (EVD-LabNet) and a laboratory assessment of chikungunya virus (CHIKV) in returning European travellers related to an ongoing outbreak in Thailand was used for this purpose. EVD-LabNet rapidly collected data on laboratory requests, diagnosed CHIKV imported cases and sequences generated, and shared among its members and with the European Centre for Disease Prevention and Control. Data across the network showed an increase in CHIKV imported cases during 1 October 2018-30 April 2019 vs the same period in 2018 (172 vs 50), particularly an increase in cases known to be related to travel to Thailand (72 vs 1). Moreover, EVD-LabNet showed that strains were imported from Thailand that cluster with strains of the ECSA-IOL E1 A226 variant emerging in Pakistan in 2016 and involved in the 2017 outbreaks in Italy. CHIKV diagnostic requests increased by 23.6% between the two periods. The impact of using EVD-LabNet or similar networks as preparedness and response tool could be improved by standardisation of the collection, quality and mining of data in routine laboratory management systems

Probabilistic reliability assessment of a heritage structure under horizontal loads

This paper proposes a methodology for the probabilistic reliability assessment of heritage buildings. The procedure addresses investigation and tests on the structure and it considers the implementation of Bayesian updating techniques for a rational use of the collected information. After having described the peculiarities of ancient buildings, it is shown how probabilistic methods can be adapted to evaluate their safety. A practical application of the methodology to a relevant case study is presented, namely a historic aqueduct in Italy. The main goal is to demonstrate the effectiveness of a probabilistic approach to the reliability assessment of heritage structures

Increasing the Robustness of the Bayesian Analysis

The reliability assessment of heritage structures represents a complex issue beyond traditional assessment procedures. Probabilistic methods and Bayesian updating techniques are often invoked in order to estimate the actual probability of failure. However a factor that should be considered is the potential bias arising with the refinement of probabilistic models. The bias may be significant if the structure has been altered during its working life and it may lead to undependable reliability assessment. In this paper a procedure that increases the robustness of the Bayesian analysis for the reliability assessment of historical buildings is presented. At the same time the process exploits probabilistic methods in order to better identify structural alteration. A practical application to a relevant case study is finally presented

Phenylpropanoids from Bupleurum fruticosum

Two new phenylpropanoids, (E)-3-(3,4-dimethoxyphenyl)-2-propen-1-yl (Z)2-[(Z)-2-methyl-2-butenoyloxymethyl]butenoate [1], and (E)-3-(4-methoxyphenyl)-2-propen-1-yl (Z)-2-[(Z)-2-methyl-2-butenoyloxymethyl]butenoate [2], were isolated from the n-hexane extract of the leaves of Bupleurum fruticosum. Their structures were established by spectral methods