[The contribution of cerebral organoids to the understanding and treatment of rare genetic diseases with neurodevelopmental disorders]. / Des organoïdes cérébraux pour la compréhension et la thérapie des maladies génétiques rares avec troubles neurodéveloppementaux.

Rare genetic diseases with neurodevelopmental disorders (NDDs) encompass several heterogeneous conditions (autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), specific learning disorder (SLD), among others). Currently, few treatments are available for these patients. The difficulty in accessing human brain samples and the discrepancies between human and animal models highlight the need for new research approaches. One promising approach is the use of the cerebral organoids. These 3D, self-organized structures, generated from induced pluripotent stem cells (iPSCs), enable the reproduction of the stages of human brain development, from the proliferation of neural stem cells to their differentiation into neurons, oligodentrocytes, and astrocytes. Cerebral organoids hold great promise in understanding brain development and in the search for treatments.

Title: Des organoïdes cérébraux pour la compréhension et la thérapie des maladies génétiques rares avec troubles neurodéveloppementaux. Abstract: Les maladies génétiques associées à des troubles neurodéveloppementaux (TND) regroupent plusieurs maladies pour lesquelles peu de traitements sont proposés. L'impossibilité d'accéder à des échantillons de cerveaux humains pour des études ex vivo, et les divergences entre l'homme et les modèles animaux rendent nécessaires de nouvelles approches de recherche. L'organoïde cérébral, une structure en trois dimensions, auto-organisée, et générée à partir de cellules souches pluripotentes induites, permet de reproduire les étapes de développement du cerveau humain, de la prolifération des cellules souches neurales à leur différenciation en neurones, en oligodendrocytes, ou en astrocytes. L'intérêt de ce modèle est désormais prouvé pour la compréhension du développement cérébral et pour la recherche de traitements. Après une présentation des cellules souches pluripotentes induites et des organoïdes, nous exposerons comment cette technique est actuellement déployée, en particulier pour étudier les mécanismes physiopathologiques résultant de variations génétiques pathogènes de gènes candidats de TND.

[A modular approach to in vivo gene therapy]. / Thérapie génique in vivo : une approche modulaire.

In vivo inactivation of a deleterious gene has been achieved in a small trial, with excellent clinical results. Interestingly, the delivery and editing system is the same as in previous work on a different disease, and the new therapy required simply changing the guide RNA used to target the Cas9 nuclease. This modular approach could be extended to a number of other genetic diseases.

Aboriginal families living with MJD in remote Australia: questions of access and equity.

Managing genetic disease using medically assisted reproductive technology is increasingly promoted as a feasible option, given revolutionary advances in genomics. Far less attention has been directed to the issue of whether there is equitable access to this option. Context and circumstance determine equitable access; however, reporting has drawn overwhelmingly from affluent Anglo-western populations in developed countries. The experiences of poorer, less educated subpopulations within affluent countries and populations in less developed countries are underreported. The ability of consumers to understand the opportunities and risks of medically assisted reproductive technology is likewise not well described in the literature despite significant technological complexity and evidence that genetic disease may be overrepresented within some disadvantaged population groups.Equity is achieved by identifying barriers and allocating appropriate resources to enable understanding and access. In the case of utilising medically assisted technology, social and power relationships, regulations, and the presumptions of authority figures and policymakers reduce equitable access. Physical or cultural marginalisation from mainstream health services may result in reduced access to genetic and prenatal testing, in-vitro fertilisation and genetic screening of embryos necessary for medically assisted reproduction. Cost and regulatory frameworks can likewise limit opportunities to engage with services. Moreover, the quality of the information provided to prospective users of the technology and how it is received governs understanding of prevention and inhibits adequately informed choice.Best practice care and adequately informed choice can only be achieved by conscientiously attending to these accessibility issues. Deep engagement with at-risk people and critical reflection on mainstream accepted standpoints is required. This paper outlines issues associated with engaging with medically assisted reproduction encountered by Aboriginal families living with Machado-Joseph Disease in some of the most remote areas of Australia. It is the right of these families to access such technologies regardless of where they live. Current barriers to access raise important questions for service providers with implications for practice as new technologies increasingly become part of standard medical care.

The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population.

There are more than 260 million people of Slavic descent worldwide, who reside mainly in Eastern Europe but also represent a noticeable share of the population in the USA and Canada. Slavic populations, particularly Eastern Slavs and some Western Slavs, demonstrate a surprisingly high degree of genetic homogeneity, and, consequently, remarkable contribution of recurrent alleles associated with hereditary diseases. Along with pan-European pathogenic variants with clearly elevated occurrence in Slavic people (e.g., ATP7B c.3207C>A and PAH c.1222C>T), there are at least 52 pan-Slavic germ-line mutations (e.g., NBN c.657_661del and BRCA1 c.5266dupC) as well as several disease-predisposing alleles characteristic of the particular Slavic communities (e.g., Polish SDHD c.33C>A and Russian ARSB c.1562G>A variants). From a clinical standpoint, Slavs have some features of a huge founder population, thus providing a unique opportunity for efficient genetic studies.

Shared etiology of Mendelian and complex disease supports drug discovery.

BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations. RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated. CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

Implementation of a dyadic nomenclature for monogenic diseases.

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease Ontology (Mondo) and Online Inheritance in Man (OMIM), formed the Disease Naming Advisory Committee (DNAC) to develop guidance for groups faced with the need to establish the "curated disease entity" for gene-phenotype validity and variant pathogenicity and to update disease names for clinical use when necessary. The objective of this group was to harmonize guidance for disease naming across these nosologic entities and among ClinGen curation groups in collaboration with other disease-related professional groups. Here, we present the initial guidance developed by the DNAC with representative examples provided by the ClinGen expert panels and working groups that warranted nomenclature updates. We also discuss the broader implications of these efforts and their benefits for harmonization of gene-disease validity curation. Overall, this work sheds light on current inconsistencies and/or discrepancies and is designed to engage the broader community on how ClinGen defines monogenic disorders using a consistent approach for disease naming.

Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach.

BACKGROUND: RNA sequencing (RNA-seq) is increasingly being used as a complementary tool to DNA sequencing in diagnostics where DNA analysis has been uninformative. RNA-seq enables the identification of aberrant splicing and aberrant gene expression, improving the interpretation of variants of unknown significance (VUSs), and provides the opportunity to scan the transcriptome for aberrant splicing and expression in relevant genes that may be the cause of a patient's phenotype. This work aims to investigate the feasibility of generating new diagnostic candidates in patients without a previously reported VUS using an RNA-seq-centric approach. METHODS: We systematically assessed the transcriptomic profiles of 86 patients with suspected Mendelian disorders, 38 of whom had no candidate sequence variant, using RNA from blood samples. Each VUS was visually inspected to search for splicing abnormalities. Once aberrant splicing was identified in cases with VUS, multiple open-source alternative splicing tools were used to investigate if they would identify what was observed in IGV. Expression outliers were detected using OUTRIDER. Diagnoses in cases without a VUS were explored using two separate strategies. RESULTS: RNA-seq allowed us to assess 71% of VUSs, detecting aberrant splicing in 14/48 patients with a VUS. We identified four new diagnoses by detecting novel aberrant splicing events in patients with no candidate sequence variants from prior DNA testing (n = 32) or where the candidate VUS did not affect splicing (n = 23). An additional diagnosis was made through the detection of skewed X-inactivation. CONCLUSION: This work demonstrates the utility of an RNA-centric approach in identifying novel diagnoses in patients without candidate VUSs. It underscores the utility of blood-based RNA analysis in improving diagnostic yields and highlights optimal approaches for such analyses.

Genetic diseases are not necessarily inherited: suggestion on its Chinese translation.

From Mendel's discovery of the basic laws of genetics in 1865 to the widespread application of genomics in medicine today, medical genetics has made enormous progress, and the concept of genetic diseases has also been evolved. In 1972, the World Health Organization (WHO) expert group began to use "Genetic Disease" to define hereditary diseases, while early Chinese genetics textbooks used "inferior inheritance", and later introduced terms such as "Genetic Disease" and "Inherited Disease". In the early days, it was generally believed that genetic diseases were inherited from ancestors. However, research in recent years has found that genetic diseases are not necessarily inherited, and some diseases are actually caused by de novo mutations in the offspring. Although the occurrence of this type of genetic disease is related to genetic factors, it is not inherited from ancestors. If we still use "Inherited Disease" or "Hereditary Disease" to describe it, it is not accurate enough. In order to further standardize the translation and use of the concept of "Genetic Disease", this article briefly reviews its development process in both English and Chinese literature, discusses the difference between different Chinese translations, and provides guidance and suggestions for scientifically and accurately describing genetic diseases in Chinese, with a view to promote efficient exchange and cooperation in the field of medical genetics.

[Genetic therapy by CRISPR-Cas: paving the way to clinical practice]. / Genetische therapie met CRISPR-Cas.

CRISPR-Cas technology is a revolutionary technology to modify DNA sequences. Owing to its effectiveness and accuracy, CRISPR-Cas holds important promises for 'genetic therapy' for various hereditary disorders. CRISPR-Cas enables researchers to modify specific parts of the genome with unprecedented precision, which, in specific cases, can be applied to correct disease-causing DNA variants. However, several important barriers are complicating the clinical implementation trajectory. There are for example concerns regarding the safety, effectiveness and ethical justification. Nevertheless, as CRISPR-Cas becomes more widely known, doctors and healthcare providers are expected to be well aware of the developments surrounding CRISPR-Cas therapy. Professional expertise and clear communication about the possibilities and limitations to patients with genetic disorders are essential, partly to avoid making promises that are unrealistic in the short term. Altogether, geneticists, medical centers and regulators are now facing the challenges to start translating CRISPR-Cas technology into clinical practice, in an effective and ethical manner.

Gene and cell therapy of human genetic diseases: Recent advances and future directions.

Disruptions in normal development and the emergence of health conditions often result from the malfunction of vital genes in the human body. Decades of scientific research have focused on techniques to modify or substitute defective genes with healthy alternatives, marking a new era in disease treatment, prevention and cure. Recent strides in science and technology have reshaped our understanding of disorders, medication development and treatment recommendations, with human gene and cell therapy at the forefront of this transformative shift. Its primary objective is the modification of genes or adjustment of cell behaviour for therapeutic purposes. In this review, we focus on the latest advances in gene and cell therapy for treating human genetic diseases, with a particular emphasis on FDA and EMA-approved therapies and the evolving landscape of genome editing. We examine the current state of innovative gene editing technologies, particularly the CRISPR-Cas systems. As we explore the progress, ethical considerations and prospects of these innovations, we gain insight into their potential to revolutionize the treatment of genetic diseases, along with a discussion of the challenges associated with their regulatory pathways. This review traces the origins and evolution of these therapies, from conceptual ideas to practical clinical applications, marking a significant milestone in the field of medical science.

Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology.

PURPOSE: The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS). METHODS: The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses. RESULTS: A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97). CONCLUSIONS: The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

Evaluating large language models on medical, lay-language, and self-reported descriptions of genetic conditions.

Large language models (LLMs) are generating interest in medical settings. For example, LLMs can respond coherently to medical queries by providing plausible differential diagnoses based on clinical notes. However, there are many questions to explore, such as evaluating differences between open- and closed-source LLMs as well as LLM performance on queries from both medical and non-medical users. In this study, we assessed multiple LLMs, including Llama-2-chat, Vicuna, Medllama2, Bard/Gemini, Claude, ChatGPT3.5, and ChatGPT-4, as well as non-LLM approaches (Google search and Phenomizer) regarding their ability to identify genetic conditions from textbook-like clinician questions and their corresponding layperson translations related to 63 genetic conditions. For open-source LLMs, larger models were more accurate than smaller LLMs: 7b, 13b, and larger than 33b parameter models obtained accuracy ranges from 21%-49%, 41%-51%, and 54%-68%, respectively. Closed-source LLMs outperformed open-source LLMs, with ChatGPT-4 performing best (89%-90%). Three of 11 LLMs and Google search had significant performance gaps between clinician and layperson prompts. We also evaluated how in-context prompting and keyword removal affected open-source LLM performance. Models were provided with 2 types of in-context prompts: list-type prompts, which improved LLM performance, and definition-type prompts, which did not. We further analyzed removal of rare terms from descriptions, which decreased accuracy for 5 of 7 evaluated LLMs. Finally, we observed much lower performance with real individuals' descriptions; LLMs answered these questions with a maximum 21% accuracy.

Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases.

Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which dominant diseases exert their effects is often experimentally challenging and resource intensive, but is essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated by conventional gene therapy, whereas DN and GOF mechanisms may require gene editing or targeting by small molecules. Moreover, pathogenic missense mutations that act via DN and GOF mechanisms are more difficult to identify than those that act via LOF using nearly all currently available variant effect predictors. Here, we introduce a tripartite statistical model made up of support vector machine binary classifiers trained to predict whether human protein coding genes are likely to be associated with DN, GOF, or LOF molecular disease mechanisms. We test the utility of the predictions by examining biologically and clinically meaningful properties known to be associated with the mechanisms. Our results strongly support that the models are able to generalise on unseen data and offer insight into the functional attributes of proteins associated with different mechanisms. We hope that our predictions will serve as a springboard for researchers studying novel variants and those of uncertain clinical significance, guiding variant interpretation strategies and experimental characterisation. Predictions for the human UniProt reference proteome are available at https://osf.io/z4dcp/.

Family Information Management in the Context of Inherited Conditions: An Integrative Review.

This review aimed to develop a framework to understand the process of information management in families with inherited conditions. Electronic databases were searched for relevant peer-reviewed articles. Articles were included if they were original research on families affected by any confirmed inherited condition, described how a family accesses, interprets, conveys, and/or uses information about the disease, included the recruitment of more than one family member, and used family as the unit of analysis. Data were analyzed through directed content analysis. Thirty-four articles from 27 studies were analyzed. We propose a framework for family information management consisting of the following domains: contextual influences, family information management behaviors, and family information management outcomes. This proposed framework expands the understanding of how families manage their genetic information in making health care decisions for their affected and at-risk relatives.

[Kidney involvement in rare hereditary diseases].

Various rare inherited disorders can be associated with kidney involvement, including glomerulopathies, tubulopathies, multiple cysts, congenital anomalies of the kidneys and urinary tract, urolithiasis, malignant and benign tumors. Genetic nephropathy should be always considered in children, adolescents and young patients with the kidneys or urinary tract disorders and/or patients with positive family anamnesis. Extrarenal manifestations can be a valuable clue for diagnosis of certain hereditary diseases, e.g. neurosensory deafness in Alport syndrome or photofobia in nephropathic cystinosis. Diagnosis of monogenic inherited diseases should be verified by genetic testing. Specific drugs are available for treatment of certain hereditary diseases involving kidney, e.g. Fabry disease, cystinosis, primary hyperoxaluria I type and atypical hemolytic uremic syndrome.

Gene therapy for ultrarare diseases: a geneticist's perspective.

Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated in more than 6000 genetic diseases; next-generation sequencing has dramatically revolutionized the diagnosis of genetic diseases. Most genetic diseases are considered very rare or ultrarare, defined here as having fewer than 1:100,000 cases, but only one of the 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three gene supplementation therapy approaches suitable for various rare genetic diseases: lentiviral vector-modified autologous CD34+ hematopoietic stem cell transplantation, systemic delivery of adeno-associated virus (AAV) vectors to the liver, and local AAV delivery to the cerebrospinal fluid and brain. Together with RNA therapies, we propose a potential business model for these gene therapies.

Inborn Errors of Immunity and Cytokine Storm Syndromes.

Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted.

Selected Monogenic Genetic Diseases in Holstein Cattle-A Review.

Genetic disorders arise from alterations in the hereditary information encoded in DNA, leading to potential detrimental effects on the well-being and vitality of organisms. Within the bovine population, genetic conditions inherited in an autosomal recessive manner are frequently associated with particular breeds. In recent years, several recessive haplotypes and a few causative mutations have been discovered in Holstein cattle: CDH (Holstein cholesterol deficiency), haplotypes with a homozygous deficiency in Holstein (HH1, HH3, HH4, HH5, HH6 and HH7), BLAD (bovine leukocyte adhesion deficiency) and DUMPS (deficiency of uridine monophosphate synthase). All of these diseases are inherited in an autosomal recessive manner. From a breeding perspective, recessive mutations specifically exhibit considerable detrimental effects and are a significant problem for breeders, exposing them to economic losses. Individual mutations can cause embryo death at any stage of pregnancy. Only genetic research and conscious selection of animals for mating will lead to a reduction in the number of carriers and elimination of mutations from the population.