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Atherosclerosis May 2020Atherosclerosis and its major clinical manifestations – myocardial infarction, ischemic stroke and peripheral artery disease – remain a leading cause of death...
Atherosclerosis and its major clinical manifestations – myocardial infarction, ischemic stroke and peripheral artery disease – remain a leading cause of death worldwide. The onset of atherosclerosis is driven by the accumulation and expansion of macrophages in the artery wall in response to lipid deposition. Subsequently, the macrophage’s failure to resolve the inflammation and to exit the plaque are key processes in the progression of atherosclerosis. Understanding the underlying causes and pathological mechanisms of this chronic, low grade inflammation that sustains plaque progression has been a major focus of the field in the last decade. In this issue of , Bruikman et al identify a rare variant in the gene encoding the neuroimmune guidance molecule netrin-1 (), in a family with premature atherosclerosis, that alters netrin-1 functions and promotes proatherogenic immune responses.
Topics: Atherosclerosis; Humans; Mutation; Netrin-1; Pedigree
PubMed: 32317107
DOI: 10.1016/j.atherosclerosis.2020.04.003 -
Bioinformatics (Oxford, England) Mar 2018The collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree...
MOTIVATION
The collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree datasets can be difficult to manage, as they are time consuming to capture, and can be difficult to build, manipulate and visualize graphically. Several standalone graphical pedigree editors and drawing applications exist but there are no freely available lightweight graphical pedigree editors that can be easily configured and incorporated into web applications.
RESULTS
We developed 'pedigreejs', an interactive graphical pedigree editor written in JavaScript, which uses standard pedigree nomenclature. Pedigreejs provides an easily configurable, extensible and lightweight pedigree editor. It makes use of an open-source Javascript library to define a hierarchical layout and to produce images in scalable vector graphics (SVG) format that can be viewed and edited in web browsers.
AVAILABILITY AND IMPLEMENTATION
The software is freely available under GPL licence (https://ccge-boadicea.github.io/pedigreejs/).
CONTACT
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Female; Humans; Internet; Male; Medical History Taking; Pedigree; Software; Web Browser
PubMed: 29095980
DOI: 10.1093/bioinformatics/btx705 -
BMC Medical Genomics Sep 2023To report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the...
PURPOSE
To report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the phenotypic features.
METHODS
5 probands with X-linked recessive related eoHM were collected in Ningxia Eye Hospital from January 2021 to June 2022. The probands and their family members received comprehensive ophthalmic examinations,and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined by Sanger sequencing and co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using silico analysis and evaluated according to ACMG guidelines. RT-qPCR was used to detect differences in the relative mRNAs expression of candidate gene in mRNAs available with the proband and family members in the pedigree 2. The relationship between genetic variants and clinical features was analyzed.
RESULTS
All probands were male, and all pedigrees conformed to an X-linked recessive inheritance pattern. They were diagnosed with high myopia at their first visits between 4 and 7 years old. Spherical equivalent ranged between - 6.00D and - 11.00D.The five novel hemizygous variants were found in the probands, containing frameshift deletion variant c.797_801del (p.Val266Alafs*75) of OPN1LW gene in the pedigree 1, nonsense variant c.513G > A (p.Trp171Ter)of RP2 gene in the pedigree 2, missense variant c.98G > T (p.Cys33Phe) of GPR143 gene in the pedigree 3, frameshift deletion variant c.1876_1877del (p.Met626Valfs*22) of FRMD7 gene in the pedigree 4 and inframe deletion variant c.670_ 675del (p.Glu192_ Glu193del) of HMGB3 gene in the pedigree 5. All variants were classified as pathogenic or likely pathogenic by the interpretation principles of HGMD sequence variants and ACMG guidelines. In family 2, RT-qPCR showed that the mRNA expression of RP2 gene was lower in the proband than in other normal family members, indicating that such variant caused an effect on gene function at the mRNA expression level. Further clinical examination showed that pedigrees 1, 2, 3, and 4 were diagnosed as X-linked recessive hereditary eye disease with early-onset high myopia, including quiescent cone dysfunction, retinitis pigmentosa, ocular albinism, and idiopathic congenital nystagmus respectively. The pedigree 5 had eoHM in the right eye and ptosis in both eyes.
CONCLUSION
In this paper,we are the first to report five novel hemizygous variants in OPN1LW, RP2, GPR143, FRMD7, HMGB3 genes are associated with eoHM. Our study extends the genotypic spectrums for eoHM and better assists ophthalmologists in assessing, diagnosing, and conducting genetic screening for eoHM.
Topics: Child; Child, Preschool; Humans; Male; Cytoskeletal Proteins; East Asian People; Genes, X-Linked; Membrane Proteins; Mutation; Myopia; Age of Onset; Exome Sequencing; Pedigree
PubMed: 37749571
DOI: 10.1186/s12920-023-01665-x -
Otolaryngology--head and Neck Surgery :... Nov 2020To evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS). (Observational Study)
Observational Study
OBJECTIVE
To evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS).
STUDY DESIGN
Retrospective observational study.
SETTING
International multicenter collaborative of >30 tertiary care centers.
METHODS
Patients with a clinically confirmed iSGS diagnosis within the North American Airway Collaborative's iSGS cohort consented between 2014 and 2018 were eligible for enrollment. Patient demographics and disease severity were abstracted from the collaborative's iSGS longitudinal registry. Pedigrees of affected families were created.
RESULTS
A total of 810 patients with iSGS were identified. Positive family history for iSGS was reported in 44 patients in 20 families. The rate of familial clustering in iSGS is 2.5%. Mean age of disease onset is 42.6 years. Of the 44 patients with familial aggregation of iSGS, 42 were female and 2 were male; 13 were mother-daughter pairs and 2 were father-daughter pairs. There were 3 sister-sister pairs. There was 1 niece-aunt pair and 2 groups of 3 family members. One pedigree demonstrated 2 affected mother-daughter pairs, with the mothers being first-degree paternal cousins. Inheritance is non-Mendelian, and anticipation is present in 11 of 13 (84%) parent-offspring pairs. The mean age of onset between parents (48.4 years) and offspring (36.1 years) was significantly different ( = .016).
CONCLUSION
This study quantifies the rate of familial clustering of iSGS at 2.5%. Inheritance is non-Mendelian, and disease demonstrates anticipation. These data suggest that there may be a genetic contribution in iSGS.
Topics: Adult; Age of Onset; Family; Female; Humans; Inheritance Patterns; Laryngostenosis; Male; Middle Aged; Patient Acuity; Pedigree; Retrospective Studies
PubMed: 32600122
DOI: 10.1177/0194599820935402 -
Molecular Ecology Resources Feb 2022In genomic-scale data sets, loci are closely packed within chromosomes and hence provide correlated information. Averaging across loci as if they were independent...
In genomic-scale data sets, loci are closely packed within chromosomes and hence provide correlated information. Averaging across loci as if they were independent creates pseudoreplication, which reduces the effective degrees of freedom (df') compared to the nominal degrees of freedom, df. This issue has been known for some time, but consequences have not been systematically quantified across the entire genome. Here, we measured pseudoreplication (quantified by the ratio df'/df) for a common metric of genetic differentiation (F ) and a common measure of linkage disequilibrium between pairs of loci (r ). Based on data simulated using models (SLiM and msprime) that allow efficient forward-in-time and coalescent simulations while precisely controlling population pedigrees, we estimated df' and df'/df by measuring the rate of decline in the variance of mean F and mean r as more loci were used. For both indices, df' increases with N and genome size, as expected. However, even for large N and large genomes, df' for mean r plateaus after a few thousand loci, and a variance components analysis indicates that the limiting factor is uncertainty associated with sampling individuals rather than genes. Pseudoreplication is less extreme for F , but df'/df ≤0.01 can occur in data sets using tens of thousands of loci. Commonly-used block-jackknife methods consistently overestimated var (F ), producing very conservative confidence intervals. Predicting df' based on our modelling results as a function of N , L, S, and genome size provides a robust way to quantify precision associated with genomic-scale data sets.
Topics: Genome Size; Genomics; Linkage Disequilibrium; Models, Genetic; Pedigree; Population Density
PubMed: 34351073
DOI: 10.1111/1755-0998.13482 -
Genetics in Medicine : Official Journal... Jun 2022This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.
PURPOSE
This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.
METHODS
Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.
RESULTS
Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).
CONCLUSION
Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.
Topics: Child; Genome; Genomics; High-Throughput Nucleotide Sequencing; Humans; Pedigree; Rare Diseases; Sequence Analysis, DNA
PubMed: 35305867
DOI: 10.1016/j.gim.2022.02.007 -
Trends in Genetics : TIG Oct 2022Some rare genetic disorders, such as retinitis pigmentosa or Alport syndrome, are caused by the co-inheritance of DNA variants at two different genetic loci (digenic... (Review)
Review
Some rare genetic disorders, such as retinitis pigmentosa or Alport syndrome, are caused by the co-inheritance of DNA variants at two different genetic loci (digenic inheritance). To capture the effects of these disease-causing variants and their possible interactive effects, various statistical methods have been developed in human genetics. Analogous developments have taken place in the field of machine learning, particularly for the field that is now called Big Data. In the past, these two areas have grown independently and have started to converge only in recent years. We discuss an overview of each of the two fields, paying special attention to machine learning methods for uncovering the combined effects of pairs of variants on human disease.
Topics: Humans; Inheritance Patterns; Machine Learning; Multifactorial Inheritance; Mutation; Pedigree
PubMed: 35581032
DOI: 10.1016/j.tig.2022.04.009 -
Fa Yi Xue Za Zhi Jun 2023Kinship testing is widely needed in forensic science practice. This paper reviews the definitions of common concepts, and summarizes the basic principles, advantages and... (Review)
Review
Kinship testing is widely needed in forensic science practice. This paper reviews the definitions of common concepts, and summarizes the basic principles, advantages and disadvantages, and application scope of kinship analysis methods, including identity by state (IBS) method, likelihood ratio (LR) method, method of moment (MoM), and identity by descent (IBD) segment method. This paper also discusses the research hotspots of challenging kinship testing, complex kinship testing, forensic genetic genealogy analysis, and non-human biological samples.
Topics: DNA Fingerprinting; Forensic Genetics; Forensic Sciences; Pedigree; Humans
PubMed: 37517010
DOI: 10.12116/j.issn.1004-5619.2023.530208 -
American Journal of Human Genetics Jul 2016Accurate estimation of shared ancestry is an important component of many genetic studies; current prediction tools accurately estimate pairwise genetic relationships up...
Accurate estimation of shared ancestry is an important component of many genetic studies; current prediction tools accurately estimate pairwise genetic relationships up to the ninth degree. Pedigree-aware distant-relationship estimation (PADRE) combines relationship likelihoods generated by estimation of recent shared ancestry (ERSA) with likelihoods from family networks reconstructed by pedigree reconstruction and identification of a maximum unrelated set (PRIMUS), improving the power to detect distant relationships between pedigrees. Using PADRE, we estimated relationships from simulated pedigrees and three extended pedigrees, correctly predicting 20% more fourth- through ninth-degree simulated relationships than when using ERSA alone. By leveraging pedigree information, PADRE can even identify genealogical relationships between individuals who are genetically unrelated. For example, although 95% of 13(th)-degree relatives are genetically unrelated, in simulations, PADRE correctly predicted 50% of 13(th)-degree relationships to within one degree of relatedness. The improvement in prediction accuracy was consistent between simulated and actual pedigrees. We also applied PADRE to the HapMap3 CEU samples and report new cryptic relationships and validation of previously described relationships between families. PADRE greatly expands the range of relationships that can be estimated by using genetic data in pedigrees.
Topics: Algorithms; Female; Haplotypes; Humans; Male; Models, Genetic; Pedigree; Reproducibility of Results
PubMed: 27374771
DOI: 10.1016/j.ajhg.2016.05.020 -
Proceedings of the National Academy of... May 2024Measuring inbreeding and its consequences on fitness is central for many areas in biology including human genetics and the conservation of endangered species. However,...
Measuring inbreeding and its consequences on fitness is central for many areas in biology including human genetics and the conservation of endangered species. However, there is no consensus on the best method, neither for quantification of inbreeding itself nor for the model to estimate its effect on specific traits. We simulated traits based on simulated genomes from a large pedigree and empirical whole-genome sequences of human data from populations with various sizes and structures (from the 1,000 Genomes project). We compare the ability of various inbreeding coefficients ([Formula: see text]) to quantify the strength of inbreeding depression: allele-sharing, two versions of the correlation of uniting gametes which differ in the weight they attribute to each locus and two identical-by-descent segments-based estimators. We also compare two models: the standard linear model and a linear mixed model (LMM) including a genetic relatedness matrix (GRM) as random effect to account for the nonindependence of observations. We find LMMs give better results in scenarios with population or family structure. Within the LMM, we compare three different GRMs and show that in homogeneous populations, there is little difference among the different [Formula: see text] and GRM for inbreeding depression quantification. However, as soon as a strong population or family structure is present, the strength of inbreeding depression can be most efficiently estimated only if i) the phenotypes are regressed on [Formula: see text] based on a weighted version of the correlation of uniting gametes, giving more weight to common alleles and ii) with the GRM obtained from an allele-sharing relatedness estimator.
Topics: Humans; Inbreeding Depression; Models, Genetic; Pedigree; Genetics, Population; Inbreeding; Alleles
PubMed: 38687793
DOI: 10.1073/pnas.2315780121