Comprehensive evaluation of the implementation of episignatures for diagnosis of neurodevelopmental disorders (NDDs)
We present a comprehensive evaluation of how the normalization of DNA methylation data affects episignature performance, using three popular classification models. We further evaluate how missing data affect those models ’ predictions. Finally, we propose a novel methodology to develop episignatures based on differentially methylated regions identification and show how this method slightly outperforms classical episignatures in the presence of missing data. (Source: Human Genetics)
Source: Human Genetics - October 27, 2023 Category: Genetics & Stem Cells Source Type: research
CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia
AbstractBeta-thalassemia (β-thalassemia) is an autosomal recessive disorder caused by point mutations, insertions, and deletions in theHBB gene cluster, resulting in the underproduction ofβ-globin chains. The most severe type may demonstrate complications including massive hepatosplenomegaly, bone deformities, and severe growth retardation in children. Treatments forβ-thalassemia include blood transfusion, splenectomy, and allogeneic hematopoietic stem cell transplantation (HSCT). However, long-term blood transfusions require regular iron removal therapy. For allogeneic HSCT, human lymphocyte antigen (HLA)-matched donor...
Source: Human Genetics - October 25, 2023 Category: Genetics & Stem Cells Source Type: research
KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster
In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused byKAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posteriorHOXC gene cluster (HOXC10,HOXC11,HOXC-AS3,HOXC-AS2, andHOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci ha...
Source: Human Genetics - October 20, 2023 Category: Genetics & Stem Cells Source Type: research
Functional implications of paralog genes in polyglutamine spinocerebellar ataxias
AbstractPolyglutamine (polyQ) spinocerebellar ataxias (SCAs) comprise a group of autosomal dominant neurodegenerative disorders caused by (CAG/CAA)n expansions. The elongated stretches of adjacent glutamines alter the conformation of the native proteins inducing neurotoxicity, and subsequent motor and neurological symptoms. Although the etiology and neuropathology of most polyQ SCAs have been extensively studied, only a limited selection of therapies is available. Previous studies on SCA1 demonstrated thatATXN1L, a human duplicated gene of the disease-associatedATXN1, alleviated neuropathology in mice models. Other SCA-ass...
Source: Human Genetics - October 16, 2023 Category: Genetics & Stem Cells Source Type: research
How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism
AbstractPrecision medicine requires precise genetic variant interpretation, yet many disease-associated genes have unresolved variants of unknown significance (VUS). We analyzed variants in a well-studied gene,FGFR1, a common cause of Idiopathic Hypogonadotropic Hypogonadism (IHH) and examined whether regional genetic enrichment of missense variants could improve variant classification.FGFR1 rare sequence variants (RSVs) were examined in a large cohort to (i) define regional genetic enrichment, (ii) determine pathogenicity based on the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) vari...
Source: Human Genetics - October 7, 2023 Category: Genetics & Stem Cells Source Type: research
Long noncoding RNAs as versatile molecular regulators of cellular stress response and homeostasis
We describe the molecular functions and physiological roles of selected lncRNAs and develop a concept of how lncRNAs can contribute as versatile players in mammalian stress response and homeostasis. These concepts may be used as a starting point for the identification of novel lncRNAs and lncRNA functions not only in the context of stress, but also in normal physiology and disease. (Source: Human Genetics)
Source: Human Genetics - October 2, 2023 Category: Genetics & Stem Cells Source Type: research
Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects
In this study, we identified two homozygous missense variants (c.986A > G, p.Y329C and c.988C > T, p.R330C) inCDC23 that are responsible for female infertility characterized by oocyte maturation defects in three infertile individuals. CDC23 (cell division cycle 23) is one of the core subunits of the APC/C. In vitro experiments showed that the variant c.986A > G (p.Y329C) led to a decrease in CDC23 protein level and the variant c.988C > T (p.R330C) changed the localization of CDC23 in HeLa cells and mouse oocytes. In vivo studies showed thatCdc23Y329C/Y329C mice successfully mimicked the pa...
Source: Human Genetics - September 28, 2023 Category: Genetics & Stem Cells Source Type: research
Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation
AbstractBrain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. This review comprehensively analyzes the key pathways and inflammatory factors related to BAVMs, and explores their interplay with epigenetic regulation and genetics. Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apop...
Source: Human Genetics - September 28, 2023 Category: Genetics & Stem Cells Source Type: research
