UNASSIGNED: For more than a century, scientists have tried to find the key to causation of mental ill health in heredity and genetics. The difficulty of finding clear and actionable answers in our genes has not stopped them looking. This history offers important context to understanding mental health science today.
UNASSIGNED: This article explores the main themes in research on genetics and inheritance in psychiatry from the second half of the nineteenth century to the present day, to address the question: what is the history of genetics as a causative explanation in mental health science? We take a critical historical approach to the literature, interrogating primary and secondary material for the light it brings to the research question, while considering the social and historical context.
UNASSIGNED: We begin with the statistics gathered in asylums and used to \'prove\' the importance of heredity in mental ill health. We then move through early twentieth century Mendelian models of mental inheritance, the eugenics movement, the influence of social psychiatry, new classifications and techniques of the postwar era, the Human Genome Project and Genome Wide Association Studies (GWAS) and epigenetics. Setting these themes in historical context shows that this research was often popular because of wider social, political and cultural issues, which impacted the views of scientists just as they did those of policymakers, journalists and the general public.
UNASSIGNED: We argue that attempting to unpick this complex history is essential to the modern ethics of mental health and genetics, as well as helping to focus our efforts to better understand causation in mental ill-health.For a succinct timeline of the history of psychiatric genetics, alongside the history of other proposed causes for mental ill-health, visit: https://historyofcauses.co.uk/.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis.
METHODS: The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives.
RESULTS: WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD.
CONCLUSIONS: The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.

We previously identified a unique genetic feature of Autism Spectrum Disorder (ASD) in human patients and established mouse models, a low to very low level of six microRNAs, miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p. We attempted to interfere experimentally in mice with two of them, miR19a-3p and miR499a-5p by microinjecting into zygote pronuclei either the complementary sequence or an excess of the microRNA. Both resulted in low levels in the tissues and sperm of the targeted microRNAs and their pri and pre precursors. This method stably modify predetermined levels of miRNAs and identify miRNA alterations that cause changes in autistic behavior and predispose the individual to an inherited disease. Excess miRNA results in single-stranded miRNA variations in both free and DNA-bound RNA (R-loop) fractions in mouse models thus appearing to affect their own transcription. Analysis of miRNAs fractions in human patients blood samples confirm low level of six microRNAs also in R-loop fractions.

BACKGROUND: Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders.
METHODS: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.
RESULTS: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%.
CONCLUSIONS: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.

BACKGROUND: Colorectal cancer in children and adolescents is an exceptional condition. Its clinical symptoms are non-specific, leading to delayed diagnosis and poor prognosis.
METHODS: The present article reports the case of a 15-year-old child followed for acute lymphoblastic leukemia with a history of a grandfather operated on and followed for colorectal cancer. The child was admitted to our department with an occlusive syndrome. Endoscopy and radiological findings suggested the diagnosis of colon adenocarcinoma (AC). The therapeutic decision was a segmental colectomy covering the right colonic angle and colostomy followed by chemotherapy.
CONCLUSIONS: Colorectal cancer remains an exceptional pathology in children. They often include abdominal pain, nausea, vomiting and rectal discharge. Endoscopy is the key diagnostic test, enabling both distal and proximal lesions to be detected. Primary CA of the colon is rare in children, and even rarer as a second malignancy.
CONCLUSIONS: The clinical symptoms of colorectal adenocarcinoma in children are non-specific. These cancers are little-known in pediatrics, and are often diagnosed at an advanced stage.

Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendel\'s laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie \"Mendelian inheritance\" of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendel\'s laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendel\'s laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading.

Endometriosis is a complex disease that affects 10-15% of women of reproductive age. Familial studies show that relatives of affected patients have a higher risk of developing the disease, implicating a genetic role for this disorder. Little is known about the impact of germline genomic copy number variant (CNV) polymorphisms on the heredity of the disease. In this study, we describe a rare CNV identified in two sisters with familial endometriosis, which contain genes that may increase the susceptibility and progression of this disease. We investigated the presence of CNVs from the endometrium and blood of the sisters with endometriosis and normal endometrium of five women as controls without the disease using array-CGH through the Agilent 2x400K platform. We excluded common CNVs that were present in the database of genomic variation. We identified, in both sisters, a rare CNV gain affecting 113kb at band 3q12.2 involving two candidate genes: ADGRG7 and TFG. The CNV gain was validated by qPCR. ADGRG7 is located at 3q12.2 and encodes a G protein-coupled receptor influencing the NF-kappaβ pathway. TFG participates in chromosomal translocations associated with hematologic tumor and soft tissue sarcomas, and is also involved in the NF-kappa B pathway. The CNV gain in this family provides a new candidate genetic marker for future familial endometriosis studies. Additional longitudinal studies of affected families must confirm any associations between this rare CNV gain and genes involved in the NF-kappaβ pathway in predisposition to endometriosis.

Heritable gene silencing has been proposed to rely on DNA methylation, histone modifications, and/or non-coding RNAs in different organisms. Here we demonstrate that multiple RNA-mediated mechanisms with distinct and easily detectable molecular signatures can underlie heritable silencing of the same open-reading frame in the nematode C. elegans. Using two-gene operons, we reveal three cases of gene-selective silencing that provide support for the transmission of heritable epigenetic changes through different mechanisms of RNA silencing independent of changes in chromatin that would affect all genes of an operon equally. Different heritable epigenetic states of a gene were associated with distinct populations of stabilized mRNA fragments with untemplated poly-UG (pUG) tails, which are known intermediates of RNA silencing. These \'pUG signatures\' provide a way to distinguish the multiple mechanisms that can drive heritable RNA silencing of a single gene.

Interacting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here, I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors, and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematode Caenorhabditis elegans. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.

In recent years, the prevalence of myopia has gradually increased, and it has become a significant global public health problem in the 21st century, posing a serious challenge to human eye health. Currently, it is confirmed that the development of myopia is attributed to the combined action of genes and environmental factors. Thus, elucidating the risk factors and pathogenesis of myopia is of great significance for the prevention and control of myopia. To elucidate the impact of gene-environment interaction on myopia, we used the Pubmed database to search for literature related to myopia. Search terms are as follows: myopia, genes, environmental factors, gene-environment interaction, and treatment. This paper reviews the effects of gene and environmental interaction on myopia.