Prenatal diagnosis in the fetal hyperechogenic kidneys: assessment using chromosomal microarray analysis and exome sequencing
AbstractFetal hyperechogenic kidneys (HEK) is etiologically a heterogeneous disorder. The aim of this study was to identify the genetic causes of HEK using prenatal chromosomal microarray analysis (CMA) and exome sequencing (ES). From June 2014 to September 2022, we identified 92 HEK fetuses detected by ultrasound. We reviewed and documented other ultrasound anomalies, microscopic and submicroscopic chromosomal abnormalities, and single gene disorders. We also analyzed the diagnostic yield of CMA and ES and the clinical impact the diagnosis had on pregnancy management. In our cohort, CMA detected 27 pathogenic copy number ...
Source: Human Genetics - April 24, 2023 Category: Genetics & Stem Cells Source Type: research
Unintended CRISPR-Cas9 editing outcomes: a review of the detection and prevalence of structural variants generated by gene-editing in human cells
AbstractGenome editing using the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein (Cas) gene-editing system (CRISPR-Cas) is a valuable tool for fundamental and applied research applications. Significant improvements in editing efficacy have advanced genome editing strategies into phase 3 human clinical trials. However, recent studies suggest that our understanding of editing outcomes has lagged behind the developments made in generating the edits themselves. While many researchers have analyzed on- and off-target events through the lens of small insertions or deletions at pre...
Source: Human Genetics - April 24, 2023 Category: Genetics & Stem Cells Source Type: research
Demographic diversity of genetic databases used in Alzheimer ’s disease research
In this study, we review published reports in academic journals of genetic studies of Alzheimer ’s disease to note whether demographic diversity was indicated in the reports and, if so, the extent of representation of non-European subjects over the period from 1997 to 2022. We use multivariate regression analysis to analyze changes over time and to explain variation across studies. Our analy sis indicates that reported diversity has not changed over time. Rather, it appears to have remained relatively constant, since Genome-Wide Association Studies (GWASs) were first used in the 1990s. We find most variation to be across...
Source: Human Genetics - April 24, 2023 Category: Genetics & Stem Cells Source Type: research
H2A monoubiquitination: insights from human genetics and animal models
AbstractMetazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of development...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
Abstract
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation D atabase (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are “variants of uncertain significance” (VUS) due to insufficient evidence for ...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
The exocyst complex in neurological disorders
AbstractExocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular space. The exocyst —an evolutionarily conserved octameric protein complex—mediates spatiotemporal control of SNARE complex assembly for vesicle fusion and tethering the secretory vesicles to the plasma membrane. The exocyst participates in diverse cellular functions, including protein trafficking to the plasma mem brane, membrane extension, cell polarity, neurite outgrowth, ciliogenesis, cytokinesis, cell migration, autophagy, host defense, and t...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
H2A monoubiquitination: insights from human genetics and animal models
AbstractMetazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of development...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
Abstract
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation D atabase (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are “variants of uncertain significance” (VUS) due to insufficient evidence for ...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
The exocyst complex in neurological disorders
AbstractExocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular space. The exocyst —an evolutionarily conserved octameric protein complex—mediates spatiotemporal control of SNARE complex assembly for vesicle fusion and tethering the secretory vesicles to the plasma membrane. The exocyst participates in diverse cellular functions, including protein trafficking to the plasma mem brane, membrane extension, cell polarity, neurite outgrowth, ciliogenesis, cytokinesis, cell migration, autophagy, host defense, and t...
Source: Human Genetics - April 22, 2023 Category: Genetics & Stem Cells Source Type: research
Proteome-wide Mendelian randomization reveals the causal effects of immune-related plasma proteins on psychiatric disorders
AbstractImmune dysregulation has been consistently reported in psychiatric disorders, however, the causes and mechanisms underlying immune dysregulation in psychiatric disorders remain largely unclear. Here we conduct a Mendelian randomization study by integrating plasma proteome and GWASs of schizophrenia, bipolar disorder and depression. The primate-specific immune-related protein BTN3A3 showed the most significant associations with all three psychiatric disorders. In addition, other immune-related proteins, including AIF1, FOXO3, IRF3, CFHR4, IGLON5, FKBP2, and PI3, also showed significant associations with psychiatric ...
Source: Human Genetics - April 21, 2023 Category: Genetics & Stem Cells Source Type: research
Specifications and validation of the ACMG/AMP criteria for clinical interpretation of sequence variants in collagen genes associated with joint hypermobility
AbstractDeleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria forCOL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 andCOL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were ...
Source: Human Genetics - April 20, 2023 Category: Genetics & Stem Cells Source Type: research
Clinical and genetic characterization of neuronal ceroid lipofuscinoses (NCLs) in 29 Iranian patients: identification of 11 novel mutations
This study aimed to identify the gene variants, molecular etiologies, and clinical features in 23 unrelated Iranian families with NCL. In total, 29 patients with neuronal ceroid lipofuscinoses (NCLs), diagnosed based on clinical manifestations, MRI neuroimaging, and electroencephalography (EEG), were recruited for this study. Through whole-exome sequencing (WES), functional prediction, Sanger sequencing, and segregation analysis, we found that 12 patients (41.3%) with mutations in the CLN6 gene, 7 patients (24%) with the TPP1 (CLN2) gene variants, and 4 patients (13.7%) with mutations in the MFSD8 (CLN7) gene. Also, mutati...
Source: Human Genetics - April 19, 2023 Category: Genetics & Stem Cells Source Type: research
High diagnostic potential of short and long read genome sequencing with transcriptome analysis in exome-negative developmental disorders
AbstractExome sequencing (ES) has become the method of choice for diagnosing rare diseases, while the availability of short-read genome sequencing (SR-GS) in a medical setting is increasing. In addition, new sequencing technologies, such as long-read genome sequencing (LR-GS) and transcriptome sequencing, are being increasingly used. However, the contribution of these techniques compared to widely used ES is not well established, particularly in regards to the analysis of non-coding regions. In a pilot study of five probands affected by an undiagnosed neurodevelopmental disorder, we performed trio-based short-read GS and l...
Source: Human Genetics - April 19, 2023 Category: Genetics & Stem Cells Source Type: research
