Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with ...adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although
mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood.
We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing.
We observed similar frequencies of rare, deleterious
mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of
mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset), and
carriers had younger mean age-of-onset compared with
carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene-damaging and predicted deleterious missense variants.
Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in
are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.
The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways ...contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD.
Insufficient bone matrix formation caused by diabetic chronic inflammation can result in bone nonunion, which is perceived as a worldwide epidemic, with a substantial socioeconomic and public health ...burden. Macrophages in microenvironment orchestrate the inflammation and launch the process of bone remodeling and repair, but aberrant activation of macrophages can drive drastic inflammatory responses during diabetic bone regeneration. In diabetes mellitus, the proliferation of resident macrophages in bone microenvironment is limited, while enhanced myeloid differentiation of hematopoietic stem cells (HSCs) leads to increased and constant monocyte recruitment and thus macrophages shift toward the classic pro-inflammatory phenotype, which leads to the deficiency of bone regeneration. In this review, we systematically summarized the anomalous origin of macrophages under diabetic conditions. Moreover, we evaluated the deficit of pro-regeneration macrophages in the diabetic inflammatory microenvironment. Finally, we further discussed the latest developments on strategies based on targeting macrophages to promote diabetic bone regeneration. Briefly, this review aimed to provide a basis for modulating the biological functions of macrophages to accelerate bone regeneration and rescue diabetic fracture healing in the future.
Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, ...and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.
To identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene.
We identified SOX17 as a novel candidate risk gene (p = 5.5e-7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases.
These data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary ...pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.
To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.
Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.
We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.
The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. ...Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.
Rare or de novo variants have substantial contribution to human diseases, but the statistical power to identify risk genes by rare variants is generally low due to rarity of genotype data. Previous ...studies have shown that risk genes usually have high expression in relevant cell types, although for many conditions the identity of these cell types are largely unknown. Recent efforts in single cell atlas in human and model organisms produced large amount of gene expression data. Here we present VBASS, a Bayesian method that integrates single-cell expression and de novo variant (DNV) data to improve power of disease risk gene discovery. VBASS models disease risk prior as a function of expression profiles, approximated by deep neural networks. It learns the weights of neural networks and parameters of Gamma-Poisson likelihood models of DNV counts jointly from expression and genetics data. On simulated data, VBASS shows proper error rate control and better power than state-of-the-art methods. We applied VBASS to published datasets and identified more candidate risk genes with supports from literature or data from independent cohorts. VBASS can be generalized to integrate other types of functional genomics data in statistical genetics analysis.
Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show ...associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals.
In silico
modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.
Accurate identification of genetic variants from next-generation sequencing (NGS) data is essential for immediate large-scale genomic endeavors such as the 1000 Genomes Project, and is crucial for ...further genetic analysis based on the discoveries. The key challenge in single nucleotide polymorphism (SNP) discovery is to distinguish true individual variants (occurring at a low frequency) from sequencing errors (often occurring at frequencies orders of magnitude higher). Therefore, knowledge of the error probabilities of base calls is essential. We have developed Atlas-SNP2, a computational tool that detects and accounts for systematic sequencing errors caused by context-related variables in a logistic regression model learned from training data sets. Subsequently, it estimates the posterior error probability for each substitution through a Bayesian formula that integrates prior knowledge of the overall sequencing error probability and the estimated SNP rate with the results from the logistic regression model for the given substitutions. The estimated posterior SNP probability can be used to distinguish true SNPs from sequencing errors. Validation results show that Atlas-SNP2 achieves a false-positive rate of lower than 10%, with an approximately 5% or lower false-negative rate.
Learning Objectives
After completing this course, the reader will be able to:
Explain the association between bisphosphonates and osteonecrosis of the jaw.
Describe the role of RBMS3 in the risk of ...BRONJ development.
This article is available for continuing medical education credit at CME.TheOncologist.com
Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction. We conducted a genomewide association study to search for genetic variants with a large effect size that increase the risk for BRONJ.
Methods.
We ascertained BRONJ cases according to the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons. We genotyped cases and a set of treatment‐matched controls using Illumina Human Omni Express 12v1 chip (733,202 markers). To maximize the power of the study, we expanded the initial control set by including population and treatment‐tolerant controls from publicly available sources. Imputation at the whole‐genome level was performed to increase the number of single nucleotide polymorphisms (SNPs) investigated. Tests of association were carried out by logistic regression, adjusting for population structure. We also examined a list of candidate genes comprising genes potentially involved in the pathogenesis of BRONJ and genes related to drug absorption, distribution, metabolism, and excretion.
Results.
Based on principal component analysis, we initially analyzed 30 white cases and 17 treatment‐tolerant controls. We subsequently expanded the control set to include 60 genetically matched controls per case. Association testing identified a significant marker in the RBMS3 gene, rs17024608 (p‐value < 7 × 10−8); individuals positive for the SNP were 5.8× more likely to develop BRONJ (odds ratio, 5.8; 95% confidence interval, 3.1–11.1). Candidate gene analysis further identified SNPs in IGFBP7 and ABCC4 as potentially implicated in BRONJ risk.
Conclusion.
Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk.
摘要.
双膦酸盐相关的颚骨坏死（BRONJ）是一种严重的药物不良反应。本实验进行了全基因组相关性研究，以寻找对BRONJ风险增加有较大影响的遗传变异。
方法. 我们根据美国口腔颌面外科医师协会的诊断标准确定了BRONJ的病例。利用Illumina人类全方位快速12v1芯片（733,202个标记物）对这些病例和接受相应治疗的对照组进行基因型检测。为了使本研究的效能最大化，我们通过从各种公开可得的来源纳入患者和治疗耐受对照，以扩大初始对照组。在全基因组水平上进行基因型填补，以增加所研究的单核苷酸多态性（SNPs）的数量。采用logistic回归分析进行相关性测试，以调整患者群体结构。我们还对一些候选基因进行了研究，包括可能参与BRONJ的发病机理的基因和与药物的吸收，分布，代谢及排泄相关的基因。
结果. 基于主要成分分析，我们初步分析了30例白种人病例和17例治疗耐受对照。随后，我们又将对照组扩大至每例病例有60个基因匹配的对照。相关性测试确定了RBMS3基因上一个显著的标记物rs17024608（p值<7×10‐8）；SNP阳性个体为5.8×，更可能诱发BRONJ（比值比，5.8; 95％置信区间3.1‐11.1）。候选基因分析进一步确定在IGFBP7和ABCC4的SNPs位点很可能诱发BRONJ风险。
结论. 我们的研究结果表明，遗传易感性在BRONJ的病理生理机制中发挥了重要的作用，而RBMS3对该不良反应的发生风险有显着影响。
A genomewide association study was conducted to search for genetic variants that increase the risk for bisphosphonate‐related osteonecrosis of the jaw. Findings suggest that genetic susceptibility plays a role in the pathophysiology of bisphosphonate‐related osteonecrosis of the jaw, with RBMS3 having a significant effect in the risk.
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