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2.
Ned Tijdschr Geneeskd ; 1682024 08 22.
Artigo em Holandês | MEDLINE | ID: mdl-39228326

RESUMO

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.


Assuntos
Sistemas CRISPR-Cas , Terapia Genética , Humanos , Terapia Genética/métodos , Terapia Genética/ética , Doenças Genéticas Inatas/terapia
3.
Int J Mol Sci ; 25(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39273284

RESUMO

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.


Assuntos
Alelos , Predisposição Genética para Doença , Humanos , Genética Populacional , População Branca/genética , Frequência do Gene , Mutação em Linhagem Germinativa , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/epidemiologia
4.
Am J Hum Genet ; 111(9): 1810-1818, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39241757

RESUMO

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.


Assuntos
Doenças Genéticas Inatas , Terminologia como Assunto , Humanos , Doenças Genéticas Inatas/genética , Bases de Dados Genéticas , Fenótipo
5.
Yi Chuan ; 46(9): 673-676, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39275867

RESUMO

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.


Assuntos
Doenças Genéticas Inatas , Doenças Genéticas Inatas/genética , Humanos , China , Terminologia como Assunto
6.
J Cell Mol Med ; 28(17): e70056, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39245805

RESUMO

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.


Assuntos
Sistemas CRISPR-Cas , Terapia Baseada em Transplante de Células e Tecidos , Edição de Genes , Doenças Genéticas Inatas , Terapia Genética , Humanos , Terapia Genética/métodos , Doenças Genéticas Inatas/terapia , Doenças Genéticas Inatas/genética , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/tendências , Edição de Genes/métodos , Animais
7.
BMC Med Genomics ; 17(1): 228, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256819

RESUMO

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.


Assuntos
Descoberta de Drogas , Humanos , Predisposição Genética para Doença , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/tratamento farmacológico , Comorbidade
8.
Genome Med ; 16(1): 110, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39252027

RESUMO

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.


Assuntos
Doenças Genéticas Inatas , Humanos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Análise de Sequência de RNA/métodos , Transcriptoma , Processamento Alternativo , Splicing de RNA
9.
Genes (Basel) ; 15(8)2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39202412

RESUMO

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.


Assuntos
Doenças dos Bovinos , Bovinos/genética , Animais , Doenças dos Bovinos/genética , Mutação , Haplótipos , Cruzamento , Doenças Genéticas Inatas/genética , Feminino , Síndrome da Aderência Leucocítica Deficitária/genética , Síndrome da Aderência Leucocítica Deficitária/veterinária
10.
Adv Exp Med Biol ; 1448: 185-207, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39117816

RESUMO

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.


Assuntos
Síndrome da Liberação de Citocina , Humanos , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Animais , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia
11.
Am J Hum Genet ; 111(9): 1819-1833, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39146935

RESUMO

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.


Assuntos
Autorrelato , Humanos , Idioma , Doenças Genéticas Inatas/genética
12.
J Fam Nurs ; 30(3): 232-254, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39194163

RESUMO

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.


Assuntos
Família , Humanos , Família/psicologia , Gestão da Informação , Feminino , Masculino , Doenças Genéticas Inatas/psicologia , Adulto , Pessoa de Meia-Idade , Idoso
13.
BMC Med Genomics ; 17(1): 214, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39160549

RESUMO

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.


Assuntos
Doenças Genéticas Inatas , Técnicas de Reprodução Assistida , Humanos , Feminino , Masculino , Doenças Genéticas Inatas/genética , Adulto , Heterozigoto , Triagem de Portadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Testes Genéticos
14.
PLoS One ; 19(8): e0307312, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39172982

RESUMO

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/.


Assuntos
Doenças Genéticas Inatas , Proteoma , Humanos , Doenças Genéticas Inatas/genética , Máquina de Vetores de Suporte , Genes Dominantes , Mutação de Sentido Incorreto , Mutação com Ganho de Função , Mutação com Perda de Função
15.
Ter Arkh ; 96(6): 559-564, 2024 Jul 07.
Artigo em Russo | MEDLINE | ID: mdl-39106495

RESUMO

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.


Assuntos
Nefropatias , Doenças Raras , Humanos , Nefropatias/diagnóstico , Nefropatias/genética , Nefropatias/etiologia , Testes Genéticos/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/complicações
16.
J Biomed Sci ; 31(1): 79, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138523

RESUMO

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.


Assuntos
Dependovirus , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Terapia Genética/métodos , Humanos , Dependovirus/genética , Vetores Genéticos , Doenças Genéticas Inatas/terapia , Doenças Genéticas Inatas/genética , Doenças Raras/terapia , Doenças Raras/genética , Lentivirus/genética
17.
J Clin Immunol ; 44(7): 165, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052144

RESUMO

More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, 47.9% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried "Slavic" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enrich genetic databases.


Assuntos
Testes Genéticos , Humanos , Feminino , Masculino , Criança , Pré-Escolar , Lactente , Estudos de Coortes , Federação Russa/epidemiologia , Adolescente , Mutação/genética , Recém-Nascido , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/epidemiologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/diagnóstico , Predisposição Genética para Doença
18.
Nat Genet ; 56(9): 1772-1779, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39075210

RESUMO

Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a 'phenotype-first' approach. This approach substantially overestimates the penetrance of variants because of ascertainment bias. The recent availability of whole-genome sequencing data in individuals from very-large-scale population-based cohorts now allows 'genotype-first' estimates of penetrance for many conditions. Although this type of population-based study can underestimate penetrance owing to recruitment biases, it provides more accurate estimates of penetrance for secondary or incidental findings. Here, we provide guidance for the conduct of penetrance studies to ensure that robust genotypes and phenotypes are used to accurately estimate penetrance of variants and groups of similarly annotated variants from population-based studies.


Assuntos
Predisposição Genética para Doença , Penetrância , Fenótipo , Humanos , Estudos de Coortes , Variação Genética , Genótipo , Testes Genéticos/métodos , Doenças Genéticas Inatas/genética , Sequenciamento Completo do Genoma/métodos
19.
Exp Mol Med ; 56(8): 1816-1825, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39085356

RESUMO

Effective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe; where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2'-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrated the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the chemical composition of oligonucleotides and suggest a fast, efficient, and feasible approach for developing personalized therapeutic interventions for genetic disorders within short time frames.


Assuntos
Mutação , Oligonucleotídeos Antissenso , Splicing de RNA , Doenças Raras , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/genética , Doenças Raras/genética , Doenças Raras/tratamento farmacológico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Morfolinos/uso terapêutico , Morfolinos/genética
20.
J Transl Med ; 22(1): 644, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982507

RESUMO

BACKGROUND: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent-offspring trios and proband only analysis. METHODS: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. RESULTS: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. CONCLUSION: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.


Assuntos
Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Doenças Genéticas Inatas , Humanos , Variações do Número de Cópias de DNA/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Reprodutibilidade dos Testes , Feminino , Valor Preditivo dos Testes , Masculino , Estudos Retrospectivos
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