Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum.

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria

Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme

In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN-treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures

Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification

Introduction Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed. Methods Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences. Results We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2). Conclusions These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility

Clinical testing panels for ALS: global distribution, consistency, and challenges

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families

Resolving conflicting LDLR variants in ClinVar - Progress of the ClinGen familial hypercholesterolemia variant curation expert panel

Abstract publicado em: https://doi.org/10.1016/j.atherosclerosis.2023.06.716Familial hypercholesterolemia (FH) is the most common monogenic disorder of lipid metabolism. Genetic testing can confirm the clinical diagnosis, but there are currently over 3300 different variants in LDLR deposited in ClinVar and ~400 had conflicting classifications of pathogenicity. Here, we present the progress of LDLR variant classification by the FH Variant Curation Expert Panel (VCEP), composed of 13 reviewers, 17 curators, and 12 associated labs, with our LDLR consensus variant classification guidelines. Variants with conflicting classifications and other variants in the same codon (required to properly classify conflicting variants) are prioritized. Associated labs send internal variant case-level data, which is uploaded into the Variant Curation Interface (VCI) and supplemented by literature evidence. Each variant is assessed by one (very experienced) or two curators and approved by three reviewers before being officially published to ClinVar. As of December 2022, we have completed classification of 316 LDLR variants. Of those with prior conflicting classifications (n=165), 33% were classified as Pathogenic/Likely pathogenic (P/LP), 9% as Benign/Likely benign (B/LB), 55% as Variant of Uncertain Significance (VUS) by insufficient evidence and only 3% remained conflicting. Of the remaining 135 variants, 53% were classified as P/LP, 2% as B/LB and 45% as VUS. Until May 2023, we will evaluate 451 LDLR variants, 247 of them with prior conflicting classifications. Ultimately, efforts of the FH VCEP are aimed at improving FH genetic diagnosis, which relies on accurate LDLR variant classification. FH VCEP’s guidelines significantly decrease conflicting classifications, which will be especially helpful to the FH community.N/

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations

Evaluating gene-disease relationships in motile ciliopathies: an international ClinGen and BEAT-PCD ERS CRC collaboration.

International audienceGenetic diagnosis of motile ciliopathies is conducted by healthcare, commercial and private laboratories. 88 genes have been implicated in motile ciliopathies (PCD, male infertility and associated disorders). Gene-disease relationships are uncertain where evidence is limited, risking inaccurate reporting and diagnosis. The ClinGen Motile Ciliopathy Gene Curation Expert Panel (GCEP) was set up collaboratively with BEAT-PCD ERS CRC in 2021. The GCEP comprises geneticists, pulmonologists and biocurators (Canada, France, Germany, Norway, Poland, Spain, Tunisia, UK, USA) tasked with classifying clinical validity of gene-disease relationships in motile ciliopathies to aid interpretation of genetic results. As an early step, the GCEP drew up guidelines to capturethe critical details of motile ciliopathy cases and to score genetic and experimental evidence conservatively and consistently. The GCEP meets monthly and so far has curated 33 gene-disease relationships (https://clinicalgenome.org/affiliation/40102/). 22 curations have reached a definitive classification as the role of the gene in disease has been repeatedly demonstrated and upheld over time, 4 were disputed.Classification PCD Infertility PCD InfertilityDefinitive CCDC39 CCDC40 CCDC103 CCNO CFAP43 DNAH1 DNAH17 CFAP300 DNAAF3 DNAH11 DNAH5 DNAI1 DNAI2 HYDIN MCIDAS ODAD1 ODAD2 ODAD4 RSPH1 RSPH4A SPAG1 ZMYND10Strong FOXJ1 DNAH8Limited CFAP57 DNAH1 DNAL1 GAS2L2 CFAP47These efforts provide a basis for future classifications of gene-disease relationships. The goal of the GCEP is to leverage emerging research to enhance the reliability of genetic testing for improved clinical detection and diagnosis of motile ciliopathies