Homozygous loss-of-function variants in FILIP1 cause autosomal recessive arthrogryposis multiplex congenita with microcephaly
AbstractArthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts of the body. Neurological and muscular disorders are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Using exome sequencing, we identified homozygou...
Source: Human Genetics - March 21, 2023 Category: Genetics & Stem Cells Source Type: research

Toward a comprehensive catalog of regulatory elements
AbstractRegulatory elements are the genomic regions that interact with transcription factors to control cell-type-specific gene expression in different cellular environments. A precise and complete catalog of functional elements encoded by the human genome is key to understanding mammalian gene regulation. Here, we review the current state of regulatory element annotation. We first provide an overview of assays for characterizing functional elements, including genome, epigenome, transcriptome, three-dimensional chromatin interaction, and functional validation assays. We then discuss computational methods for defining regul...
Source: Human Genetics - March 19, 2023 Category: Genetics & Stem Cells Source Type: research

Loss of SUN1 function in spermatocytes disrupts the attachment of telomeres to the nuclear envelope and contributes to non-obstructive azoospermia in humans
AbstractOne of the most severe forms of infertility in humans, caused by gametogenic failure, is non-obstructive azoospermia (NOA). Approximately, 20 –30% of men with NOA may have single-gene mutations or other genetic variables that cause this disease. While a range of single-gene mutations associated with infertility has been identified in prior whole-exome sequencing (WES) studies, current insight into the precise genetic etiology of impaire d human gametogenesis remains limited. In this paper, we described a proband with NOA who experienced hereditary infertility. WES analyses identified a homozygous variant in theSU...
Source: Human Genetics - March 18, 2023 Category: Genetics & Stem Cells Source Type: research

Enrichment of self-domestication and neural crest function loci in the heritability of neurodevelopmental disorders
AbstractSelf-domestication could contribute to shaping the biology of human brain and consequently the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spectrum disorder, schizophrenia (SCZ in East Asian and European ancestries, EAS and EUR, respectively), attention-deficit/hyperactivity disorder, obsessive –compulsive disorder, and Tourette’s syndrome (TS). Considering only self-domestication and neural-crest-function annotations i...
Source: Human Genetics - March 17, 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

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