Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins
AbstractNuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose “nuclear speckleopathies”. Notably, developmental disabilitie...
Source: Human Genetics - March 16, 2023 Category: Genetics & Stem Cells Source Type: research
CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome
The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants inCRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare...
Source: Human Genetics - March 16, 2023 Category: Genetics & Stem Cells Source Type: research
Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins
AbstractNuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose “nuclear speckleopathies”. Notably, developmental disabilitie...
Source: Human Genetics - March 16, 2023 Category: Genetics & Stem Cells Source Type: research
CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome
The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants inCRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare...
Source: Human Genetics - March 16, 2023 Category: Genetics & Stem Cells Source Type: research
Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders
AbstractAge-related macular degeneration (AMD), cataract, and glaucoma are leading causes of blindness worldwide. Previous genome-wide association studies (GWASs) have revealed a variety of susceptible loci associated with age-related ocular disorders, yet the genetic pleiotropy and causal genes across these diseases remain poorly understood. By leveraging large-scale genetic and observational data from ocular disease GWASs and UK Biobank (UKBB), we found significant pairwise genetic correlations and consistent epidemiological associations among these ocular disorders. Cross-disease meta-analysis uncovered seven pleiotropi...
Source: Human Genetics - March 14, 2023 Category: Genetics & Stem Cells Source Type: research
VIsoQLR: an interactive tool for the detection, quantification and fine-tuning of isoforms in selected genes using long-read sequencing
AbstractDNA variants altering the pre-mRNA splicing process represent an underestimated cause of human genetic diseases. Their association with disease traits should be confirmed using functional assays from patient cell lines or alternative models to detect aberrant mRNAs. Long-read sequencing is a suitable technique to identify and quantify mRNA isoforms. Available isoform detection and/or quantification tools are generally designed for the whole transcriptome analysis. However experiments focusing on genes of interest need more precise data fine-tuning and visualization tools.Here we describe VIsoQLR, an interactive ana...
Source: Human Genetics - March 7, 2023 Category: Genetics & Stem Cells Source Type: research
oFlowSeq: a quantitative approach to identify protein coding mutations affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids
AbstractCerebral organoids are comprised of diverse cell types found in the developing human brain, and can be leveraged in the identification of critical cell types perturbed by genetic risk variants in common, neuropsychiatric disorders. There is great interest in developing high-throughput technologies to associate genetic variants with cell types. Here, we describe a high-throughput, quantitative approach (oFlowSeq) by utilizing CRISPR-Cas9, FACS sorting, and next-generation sequencing. Using oFlowSeq, we found that deleterious mutations in autism-associated geneKCTD13 resulted in increased proportions of Nestin+ cells...
Source: Human Genetics - March 6, 2023 Category: Genetics & Stem Cells Source Type: research
Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species
AbstractThere has been considerable recent interest in the role that germline variants in histone genes play in Mendelian syndromes. Specifically, missense variants inH3-3A andH3-3B, which both encode Histone 3.3, were discovered to cause a novel neurodevelopmental disorder, Bryant-Li-Bhoj syndrome. Most of the causative variants are private and scattered throughout the protein, but all seem to have either a gain-of-function or dominant negative effect on protein function. This is highly unusual and not well understood. However, there is extensive literature about the effects of Histone 3.3 mutations in model organisms. He...
Source: Human Genetics - March 3, 2023 Category: Genetics & Stem Cells Source Type: research
TMEM151A variants associated with paroxysmal kinesigenic dyskinesia
AbstractTMEM151A, located at 11q13.2 and encoding transmembrane protein 151A, was recently reported as causative for autosomal dominant paroxysmal kinesigenic dyskinesia (PKD). Here, through comprehensive analysis of sporadic and familial cases, we expand the clinical and mutation spectrum of PKD. In doing so, we clarify the clinical and genetic features of Chinese PKD patients harboringTMEM151A variants and further explore the relationship betweenTMEM151A mutations and PKD. Whole exome sequencing was performed on 26 sporadic PKD patients and nine familial PKD pedigrees withoutPRRT2 variants. Quantitative real-time PCR was...
Source: Human Genetics - March 1, 2023 Category: Genetics & Stem Cells Source Type: research
Biallelic SHQ1 variants in early infantile hypotonia and paroxysmal dystonia as the leading manifestation
AbstractBiallelicSHQ1 variant-related neurodevelopmental disorder is extremely rare. To date, only six affected individuals, from four families, have been reported. Here, we report eight individuals, from seven unrelated families, who exhibited neurodevelopmental disorder and/or dystonia, received whole-genome sequencing, and had inherited biallelicSHQ1 variants. The median age at disease onset was 3.5 months old. All eight individuals exhibited normal eye contact, profound hypotonia, paroxysmal dystonia, and brisk deep tendon reflexes at the first visit. Varying degrees of autonomic dysfunction were observed. One indivi...
Source: Human Genetics - February 27, 2023 Category: Genetics & Stem Cells Source Type: research
