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Nature Genetics Jul 2023The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian...
The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.
Topics: Humans; Genome-Wide Association Study; Veterans; Pedigree; Aortic Aneurysm, Thoracic; Aortic Dissection
PubMed: 37308786
DOI: 10.1038/s41588-023-01420-z -
Science (New York, N.Y.) Mar 2024We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at...
We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.
Topics: Humans; Autoimmunity; Cell Differentiation; Homozygote; Intraepithelial Lymphocytes; Receptors, Antigen, T-Cell, alpha-beta; Membrane Glycoproteins; Loss of Function Mutation; Lymphocyte Count; Alleles; Infections; Lymphoproliferative Disorders; Pedigree; Male; Female; Middle Aged; Aged; Aged, 80 and over
PubMed: 38422122
DOI: 10.1126/science.adh4059 -
Bioinformatics (Oxford, England) Jul 2023The resemble between relatives computed from pedigree and genomic data is an important resource for geneticists and ecologists, who are interested in understanding how...
MOTIVATION
The resemble between relatives computed from pedigree and genomic data is an important resource for geneticists and ecologists, who are interested in understanding how genes influence phenotypic variation, fitness adaptation, and population dynamics.
RESULTS
The AGHmatrix software is an R package focused on the construction of pedigree (A matrix) and/or molecular markers (G matrix), with the possibility of building a combined matrix of pedigree corrected by molecular markers (H matrix). Designed to estimate the relationships for any ploidy level, the software also includes auxiliary functions related to filtering molecular markers, and checks pedigree errors in large data sets. After computing the relationship matrices, results from the AGHmatrix can be used in different contexts, including on prediction of (genomic) estimated breeding values and genome-wide association studies.
AVAILABILITY AND IMPLEMENTATION
AGHmatrix v2.1.0 is available under GPL-3 license in CRAN at https://cran.r-project.org/web/packages/AGHmatrix/index.html and also in GitHub at https://github.com/rramadeu/AGHmatrix. It has a comprehensive tutorial, and it follows with real data examples.
Topics: Genome-Wide Association Study; Software; Genomics; Ploidies; Pedigree
PubMed: 37471595
DOI: 10.1093/bioinformatics/btad445 -
World Journal of Pediatrics : WJP Jul 2023Hirschsprung's disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction... (Review)
Review
BACKGROUND
Hirschsprung's disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance. We still do not know the penetrance and genetic characteristics of these known risk genes due to the rarity of HSCR families.
METHODS
To find published references, we used the title/abstract terms "Hirschsprung" and "familial" in the PubMed database and the MeSH terms "Hirschsprung" and "familial" in Web of Science. Finally, we summarized 129 HSCR families over the last 40 years.
RESULTS
The male-to-female ratio and the percentage of short segment-HSCR in familial HSCR are much lower than in sporadic HSCR. The primary gene factors in the syndromic families are ret proto-oncogene (RET) and endothelin B receptor gene (EDNRB). Most families show incomplete dominance and are relevant to RET, and the RET mutation has 56% penetrance in familial HSCR. When one of the parents is a RET mutation carrier in an HSCR family, the offspring's recurrence risk is 28%, and the incidence of the offspring does not depend on whether the parent suffers from HSCR.
CONCLUSION
Our findings will help HSCR patients obtain better genetic counseling, calculate the risk of recurrence, and provide new insights for future pedigree studies.
Topics: Humans; Male; Female; Hirschsprung Disease; Proto-Oncogene Proteins c-ret; Mutation; Pedigree
PubMed: 36857021
DOI: 10.1007/s12519-023-00686-x -
Circulation. Genomic and Precision... Oct 2023Variants in the gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart...
BACKGROUND
Variants in the gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed.
METHODS
Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood.
RESULTS
Four pathogenic/likely pathogenic variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen variant-negative probands (15/40: 37.5%) had variants in autosomal genes including , , , and . Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls.
CONCLUSIONS
Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if -associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.
Topics: Adult; Humans; Male; Female; Dystrophin; Comparative Genomic Hybridization; Pedigree; Genotype; Phenotype; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins
PubMed: 37671549
DOI: 10.1161/CIRCGEN.123.004221 -
Genetics in Medicine : Official Journal... Sep 20235-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the...
PURPOSE
5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive.
METHODS
We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene.
RESULTS
We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment.
CONCLUSION
Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
Topics: Humans; Intellectual Disability; Homozygote; Neurodevelopmental Disorders; Methyltransferases; RNA; Pedigree; tRNA Methyltransferases
PubMed: 37226891
DOI: 10.1016/j.gim.2023.100900 -
BMC Genomics Jul 2023Pedigree-based inbreeding coefficients have been generally included in statistical models for genetic evaluation of Japanese Black cattle. The use of genomic data is...
BACKGROUND
Pedigree-based inbreeding coefficients have been generally included in statistical models for genetic evaluation of Japanese Black cattle. The use of genomic data is expected to provide precise assessment of inbreeding level and depression. Recently, many measures have been used for genome-based inbreeding coefficients; however, with no consensus on which is the most appropriate. Therefore, we compared the pedigree- ([Formula: see text]) and multiple genome-based inbreeding coefficients, which were calculated from the genomic relationship matrix with observed allele frequencies ([Formula: see text]), correlation between uniting gametes ([Formula: see text]), the observed vs expected number of homozygous genotypes ([Formula: see text]), runs of homozygosity (ROH) segments ([Formula: see text]) and heterozygosity by descent segments ([Formula: see text]). We quantified inbreeding depression from estimating regression coefficients of inbreeding coefficients on three reproductive traits: age at first calving (AFC), calving difficulty (CD) and gestation length (GL) in Japanese Black cattle.
RESULTS
The highest correlations with [Formula: see text] were for [Formula: see text] (0.86) and [Formula: see text] (0.85) whereas [Formula: see text] and [Formula: see text] provided weak correlations with [Formula: see text], with range 0.33-0.55. Except for [Formula: see text] and [Formula: see text], there were strong correlations among genome-based inbreeding coefficients ([Formula: see text] 0.94). The estimates of regression coefficients of inbreeding depression for [Formula: see text] was 2.1 for AFC, 0.63 for CD and -1.21 for GL, respectively, but [Formula: see text] had no significant effects on all traits. Genome-based inbreeding coefficients provided larger effects on all reproductive traits than [Formula: see text]. In particular, for CD, all estimated regression coefficients for genome-based inbreeding coefficients were significant, and for GL, that for [Formula: see text] had a significant.. Although there were no significant effects when using overall genome-level inbreeding coefficients for AFC and GL, [Formula: see text] provided significant effects at chromosomal level in four chromosomes for AFC, three chromosomes for CD, and two chromosomes for GL. In addition, similar results were obtained for [Formula: see text].
CONCLUSIONS
Genome-based inbreeding coefficients can capture more phenotypic variation than [Formula: see text]. In particular, [Formula: see text] and [Formula: see text] can be considered good estimators for quantifying inbreeding level and identifying inbreeding depression at the chromosome level. These findings might improve the quantification of inbreeding and breeding programs using genome-based inbreeding coefficients.
Topics: Animals; Cattle; Inbreeding; Inbreeding Depression; Pedigree; Polymorphism, Single Nucleotide; Genotype; Genomics; Homozygote
PubMed: 37403068
DOI: 10.1186/s12864-023-09480-5 -
Nature Communications Aug 2023High-quality whole-genome resequencing in large-scale pig populations with pedigree structure and multiple breeds would enable accurate construction of haplotype and...
High-quality whole-genome resequencing in large-scale pig populations with pedigree structure and multiple breeds would enable accurate construction of haplotype and robust selection-signature detection. Here, we sequence 740 pigs, combine with 149 of our previously published resequencing data, retrieve 207 resequencing datasets, and form a panel of worldwide distributed wild boars, aboriginal and highly selected pigs with pedigree structures, amounting to 1096 genomes from 43 breeds. Combining with their haplotype-informative reads and pedigree structure, we accurately construct a panel of 1874 haploid genomes with 41,964,356 genetic variants. We further demonstrate its valuable applications in GWAS by identifying five novel loci for intramuscular fat content, and in genomic selection by increasing the accuracy of estimated breeding value by 36.7%. In evolutionary selection, we detect MUC13 gene under a long-term balancing selection, as well as NPR3 gene under positive selection for pig stature. Our study provides abundant genomic variations for robust selection-signature detection and accurate haplotypes for deciphering complex traits in pigs.
Topics: Sus scrofa; Animals; Whole Genome Sequencing; Genetic Variation; Genome-Wide Association Study; Mucins; Selection, Genetic; Body Size
PubMed: 37612277
DOI: 10.1038/s41467-023-40434-3 -
Vision Research Dec 2023Mutations in pre-mRNA processing factor 31 cause autosomal dominant retinitis pigmentosa (PRPF31-RP), for which there is currently no efficient treatment, making this... (Review)
Review
Mutations in pre-mRNA processing factor 31 cause autosomal dominant retinitis pigmentosa (PRPF31-RP), for which there is currently no efficient treatment, making this disease a prime target for the development of novel therapeutic strategies. PRPF31-RP exhibits incomplete penetrance due to haploinsufficiency, in which reduced levels of gene expression from the mutated allele result in disease. A variety of model systems have been used in the investigation of disease etiology and therapy development. In this review, we discuss recent advances in both in vivo and in vitro model systems, evaluating their advantages and limitations in the context of therapy development for PRPF31-RP. Additionally, we describe the latest approaches for treatment, including AAV-mediated gene augmentation, genome editing, and late-stage therapies such as optogenetics, cell transplantation, and retinal prostheses.
Topics: Humans; Mutation; Retinitis Pigmentosa; Eye Proteins; Pedigree
PubMed: 37714045
DOI: 10.1016/j.visres.2023.108315 -
Tremor and Other Hyperkinetic Movements... 2023Genetic factors have been implicated in the pathogenesis of blepharospasm (BSP), a dystonia characterized by excessive blinking and involuntary eyelid closure. Previous...
BACKGROUND
Genetic factors have been implicated in the pathogenesis of blepharospasm (BSP), a dystonia characterized by excessive blinking and involuntary eyelid closure. Previous research identified a co-segregating deleterious variant (GRCh38/hg38, NC_000009.12: g.127733410G>A, NM_001085347.3:c.568C>T, p. Arg190Cys) in three subjects with BSP and three carriers within a multi-generation pedigree. Other variants have been reported in patients with dystonia.
METHODS
Sanger sequencing was used to screen a cohort of 307 subjects with isolated BSP or BSP-plus dystonia affecting additional anatomical segments (BSP+). We also utilized computational tools to uniformly assess the deleteriousness and potential pathogenicity of previously reported variants.
RESULTS
There were no highly deleterious variants in the coding or contiguous splice site regions of within our cohort of 307 subjects.
DISCUSSION
Highly deleterious variants in are rare in patients with BSP/BSP+ phenotypes.
HIGHLIGHTS
Over 300 patients with BSP were screened for variants in , a (DYT1) homologue. No highly deleterious variants were identified in our cohort. The role of in BSP and other forms of dystonia remains indeterminant.
Topics: Humans; Blepharospasm; Dystonia; Dystonic Disorders; Molecular Chaperones; Pedigree
PubMed: 38076033
DOI: 10.5334/tohm.825