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Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population. 基于新一代测序技术的大规模沙特人群 SLCO1B1 药物遗传学变异分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-25 DOI: 10.1186/s40246-024-00594-9
Ewa Goljan, Mohammed Abouelhoda, Asma Tahir, Mohamed ElKalioby, Brian Meyer, Dorota Monies

Background: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East.

Methods: The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC).

Results: We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations.

Conclusions: The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.

背景:SLCO1B1 在介导他汀类药物、血管紧张素转换酶抑制剂、化疗药物和抗生素等多种不同药物的肝清除过程中发挥着重要作用。研究表明,SLCO1B1 中的几种变异对这些药物的疗效有显著的临床影响。本研究全面概述了中东地区最大的阿拉伯人口之一--沙特人的 SLCO1B1 变异情况:方法:根据临床药理基因实施联盟(CPIC)的描述,使用 11,889 个沙特人(961 个外显子组和 1928 个药物基因组)的数据集来确定 SLCO1B1 变异的存在和频率:结果:我们发现了 141 个先前描述过的 SNPs,其中 rs2306283(50%)和 rs4149056(28%)最为常见。此外,我们还观察到六个等位基因[*15(24.7%),其次是*20(8.04%)、*14(5.86%)、*5(3.84%)、*31(0.21%)和*9(0.03%)],预测这些等位基因可用于临床。从等位基因二联型到表型的转换显示了 41 种 OATP1B1 二联型。我们估算了由 17 个此类变异导致的罕见和新型预测有害变异的负担:我们所提供的数据来自迄今为止所研究的最大的阿拉伯队列之一,这些数据最全面地概述了 SLCO1B1 变异以及该族群随后的 OATP1B1 活性,迄今为止,该族群在现有国际基因组数据库中的代表性仍然相对不足。我们相信,所提供的数据为进一步的临床研究和在阿拉伯人中应用个性化他汀类药物治疗指导奠定了基础。
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引用次数: 0
Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins. 不同来源人群中淀粉样蛋白变异的临床表现。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-25 DOI: 10.1186/s40246-024-00596-7
Antonella De Lillo, Gita A Pathak, Aislinn Low, Flavio De Angelis, Sarah Abou Alaiwi, Edward J Miller, Maria Fuciarelli, Renato Polimanti

Purpose: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations.

Methods: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank.

Results: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003).

Conclusions: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

目的:Transthyretin(TTR)基因的编码突变会导致一种遗传性淀粉样变性病,其特点是基因型与表型之间存在复杂的相关性,但有关全球人群之间差异的信息却很有限:我们比较了676名携带TTR淀粉样变性突变(rs138065384,Phe44Leu;rs730881165,Ala81Thr;rs121918074,His90Asn;rs76992529,Val122Ile)的不同个体与12430名年龄、性别和基因推断血统相匹配的非携带者,以评估他们的临床表现,这些临床表现涉及英国生物库电子健康记录中的1693项结果:在非洲裔(AFR)个体中,Val122Ile突变与循环系统相关的多种结果有关(折合富集度=2.96,p=0.002),其中关联性最强的是心脏先天性异常(phecode 747.1,p=0.003)、心内膜炎(phecode 420.3,p=0.006)和心肌病(phecode 425,p=0.007)。在中亚-南亚后裔(CSA)中,His90Asn突变与皮肤病结果相关(富集倍数=28,p=0.001)。在欧洲后裔(EUR,富集倍数=3.09,p=0.003)中,同样的TTR突变与肿瘤有关。在欧洲人中,Ala81Thr 与呼吸系统结果有多种关联(折合富集度 = 3.61,p = 0.002),但最强的关联是房室传导阻滞(phecode 426.2,p = 2.81 × 10-4)。此外,东亚人(EAS)的相同突变与内分泌代谢特征也有关联(折合富集度 = 4.47,p = 0.003)。在跨宗族荟萃分析中,Val122Ile突变与周围神经疾病(phecode 351,p = 0.004)有关,此外还与心脏先天性异常有关(fold-enrichment = 6.94,p = 0.003):总之,这些研究结果表明,TTR淀粉样变性突变与一系列健康领域存在祖先特异性和祖先融合性关联。这表明有必要提高全球人群对 TTR 突变相关结果的认识,以减少 TTR 相关淀粉样变性病的误诊和延迟诊断。
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引用次数: 0
Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency. 结构重排是 SETBP1 单倍体缺乏症反复出现的致病机制。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-22 DOI: 10.1186/s40246-024-00600-0
V Alesi, S Genovese, M C Roberti, E Sallicandro, S Di Tommaso, S Loddo, V Orlando, D Pompili, C Calacci, V Mei, E Pisaneschi, M V Faggiano, A Morgia, C Mammì, G Astrea, R Battini, M Priolo, M L Dentici, R Milone, A Novelli

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.

染色体结构重排包括基因组结构的异常,可能与遗传物质的增减有关,也可能无关。从诊断的角度来看,评估精确的断点至关重要,它可以突出可能的基因干扰,并解决适当的基因型与表型的关联问题。结构重排既可能在基因组内随机发生,也可能反复出现,这主要是由于周围区域的基因组特征特殊。我们报告了三个非亲缘关系的个体,他们的染色体结构重排中断了 SETBP1,导致基因单倍性缺陷。其中两人的染色体微阵列分析(CMA)结果为阴性,在微阵列分辨率下重排是平衡的。第三例出现了复杂的三染色体重排,之前曾被诊断为 SETBP1 单倍体缺陷,原因是其中一个染色体断点上存在部分基因缺失。我们通过光学基因组图谱(OGM)和全基因组测序(WGS)对重排进行了全面鉴定,提供了所涉及序列和潜在机制的详细信息。我们认为结构变异是 SETBP1 单倍性贫血的一个经常性事件,实验室常规基因组分析(CMA 和全外显子组测序)可能会忽略这些变异,或者在断点基因组缺失时只能部分确定这些变异。最后,我们介绍了 SETBP1 在努南样表型中可能扮演的角色。
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引用次数: 0
Explicable prioritization of genetic variants by integration of rule-based and machine learning algorithms for diagnosis of rare Mendelian disorders. 通过整合基于规则的算法和机器学习算法,对遗传变异进行可解释的优先排序,以诊断罕见孟德尔疾病。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-21 DOI: 10.1186/s40246-024-00595-8
Ho Heon Kim, Dong-Wook Kim, Junwoo Woo, Kyoungyeul Lee

Background: In the process of finding the causative variant of rare diseases, accurate assessment and prioritization of genetic variants is essential. Previous variant prioritization tools mainly depend on the in-silico prediction of the pathogenicity of variants, which results in low sensitivity and difficulty in interpreting the prioritization result. In this study, we propose an explainable algorithm for variant prioritization, named 3ASC, with higher sensitivity and ability to annotate evidence used for prioritization. 3ASC annotates each variant with the 28 criteria defined by the ACMG/AMP genome interpretation guidelines and features related to the clinical interpretation of the variants. The system can explain the result based on annotated evidence and feature contributions.

Results: We trained various machine learning algorithms using in-house patient data. The performance of variant ranking was assessed using the recall rate of identifying causative variants in the top-ranked variants. The best practice model was a random forest classifier that showed top 1 recall of 85.6% and top 3 recall of 94.4%. The 3ASC annotates the ACMG/AMP criteria for each genetic variant of a patient so that clinical geneticists can interpret the result as in the CAGI6 SickKids challenge. In the challenge, 3ASC identified causal genes for 10 out of 14 patient cases, with evidence of decreased gene expression for 6 cases. Among them, two genes (HDAC8 and CASK) had decreased gene expression profiles confirmed by transcriptome data.

Conclusions: 3ASC can prioritize genetic variants with higher sensitivity compared to previous methods by integrating various features related to clinical interpretation, including features related to false positive risk such as quality control and disease inheritance pattern. The system allows interpretation of each variant based on the ACMG/AMP criteria and feature contribution assessed using explainable AI techniques.

背景:在寻找罕见病致病变异体的过程中,对遗传变异体进行准确评估和优先排序至关重要。以往的变异体优先排序工具主要依赖于对变异体致病性的体内预测,导致灵敏度低,难以解释优先排序结果。在本研究中,我们提出了一种可解释的变异优先级排序算法,命名为 3ASC,它具有更高的灵敏度和注释优先级排序所用证据的能力。3ASC 根据 ACMG/AMP 基因组解释指南定义的 28 项标准以及与变异临床解释相关的特征对每个变异进行注释。该系统可根据注释的证据和特征贡献解释结果:我们利用内部患者数据训练了各种机器学习算法。我们使用内部患者数据训练了各种机器学习算法,并使用识别排名靠前的变异中致病变异的召回率评估了变异排名的性能。最佳实践模型是随机森林分类器,其前 1 名的召回率为 85.6%,前 3 名的召回率为 94.4%。3ASC 为患者的每个基因变异注释了 ACMG/AMP 标准,这样临床遗传学家就能像在 CAGI6 SickKids 挑战赛中那样解释结果。在这次挑战中,3ASC 为 14 例患者中的 10 例确定了致病基因,为 6 例确定了基因表达减少的证据。其中,有两个基因(HDAC8 和 CASK)的基因表达减少得到了转录组数据的证实:3ASC通过整合与临床解读相关的各种特征,包括与假阳性风险相关的特征(如质量控制和疾病遗传模式),与之前的方法相比,能以更高的灵敏度对基因变异进行优先排序。该系统可根据 ACMG/AMP 标准和使用可解释人工智能技术评估的特征贡献对每个变异进行解释。
{"title":"Explicable prioritization of genetic variants by integration of rule-based and machine learning algorithms for diagnosis of rare Mendelian disorders.","authors":"Ho Heon Kim, Dong-Wook Kim, Junwoo Woo, Kyoungyeul Lee","doi":"10.1186/s40246-024-00595-8","DOIUrl":"10.1186/s40246-024-00595-8","url":null,"abstract":"<p><strong>Background: </strong>In the process of finding the causative variant of rare diseases, accurate assessment and prioritization of genetic variants is essential. Previous variant prioritization tools mainly depend on the in-silico prediction of the pathogenicity of variants, which results in low sensitivity and difficulty in interpreting the prioritization result. In this study, we propose an explainable algorithm for variant prioritization, named 3ASC, with higher sensitivity and ability to annotate evidence used for prioritization. 3ASC annotates each variant with the 28 criteria defined by the ACMG/AMP genome interpretation guidelines and features related to the clinical interpretation of the variants. The system can explain the result based on annotated evidence and feature contributions.</p><p><strong>Results: </strong>We trained various machine learning algorithms using in-house patient data. The performance of variant ranking was assessed using the recall rate of identifying causative variants in the top-ranked variants. The best practice model was a random forest classifier that showed top 1 recall of 85.6% and top 3 recall of 94.4%. The 3ASC annotates the ACMG/AMP criteria for each genetic variant of a patient so that clinical geneticists can interpret the result as in the CAGI6 SickKids challenge. In the challenge, 3ASC identified causal genes for 10 out of 14 patient cases, with evidence of decreased gene expression for 6 cases. Among them, two genes (HDAC8 and CASK) had decreased gene expression profiles confirmed by transcriptome data.</p><p><strong>Conclusions: </strong>3ASC can prioritize genetic variants with higher sensitivity compared to previous methods by integrating various features related to clinical interpretation, including features related to false positive risk such as quality control and disease inheritance pattern. The system allows interpretation of each variant based on the ACMG/AMP criteria and feature contribution assessed using explainable AI techniques.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10956189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hemorrhoidal disease and its genetic association with depression, bipolar disorder, anxiety disorders, and schizophrenia: a bidirectional mendelian randomization study. 痔疮及其与抑郁症、双相情感障碍、焦虑症和精神分裂症的遗传关联:一项双向泯灭随机研究。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-21 DOI: 10.1186/s40246-024-00588-7
Zhiguang Huang, Jian Huang, Chun Kai Leung, Casper Jp Zhang, Babatunde Akinwunmi, Wai-Kit Ming

Background: Hemorrhoids and psychiatric disorders exhibit high prevalence rates and a tendency for relapse in epidemiological studies. Despite this, limited research has explored their correlation, and these studies are often subject to reverse causality and residual confounding. We conducted a Mendelian randomization (MR) analysis to comprehensively investigate the association between several mental illnesses and hemorrhoidal disease.

Methods: Genetic associations for four psychiatric disorders and hemorrhoidal disease were obtained from large consortia, the FinnGen study, and the UK Biobank. Genetic variants associated with depression, bipolar disorder, anxiety disorders, schizophrenia, and hemorrhoidal disease at the genome-wide significance level were selected as instrumental variables. Screening for potential confounders in genetic instrumental variables using PhenoScanner V2. Bidirectional MR estimates were employed to assess the effects of four psychiatric disorders on hemorrhoidal disease.

Results: Our analysis revealed a significant association between genetically predicted depression and the risk of hemorrhoidal disease (IVW, OR=1.20,95% CI=1.09 to 1.33, P <0.001). We found no evidence of associations between bipolar disorder, anxiety disorders, schizophrenia, and hemorrhoidal disease. Inverse MR analysis provided evidence for a significant association between genetically predicted hemorrhoidal disease and depression (IVW, OR=1.07,95% CI=1.04 to 1.11, P <0.001).

Conclusions: This study offers MR evidence supporting a bidirectional causal relationship between depression and hemorrhoidal disease.

背景:在流行病学研究中,痔疮和精神疾病的发病率很高,而且有复发的趋势。尽管如此,对二者相关性的研究却十分有限,而且这些研究往往受到反向因果关系和残余混杂因素的影响。我们进行了孟德尔随机化(MR)分析,以全面研究几种精神疾病与痔疮疾病之间的关联:方法:我们从大型联盟、芬兰基因研究和英国生物库中获得了四种精神疾病与痔疮的遗传关联。选择与抑郁症、双相情感障碍、焦虑症、精神分裂症和痔疮疾病相关的全基因组显著性水平的遗传变异作为工具变量。使用 PhenoScanner V2 筛选遗传工具变量中的潜在混杂因素。采用双向 MR 估计来评估四种精神疾病对痔疮疾病的影响:我们的分析表明,遗传预测的抑郁症与痔疮疾病风险之间存在明显关联(IVW,OR=1.20,95% CI=1.09~1.33,P 结论:该研究提供了支持双向MR估计的证据:本研究提供了 MR 证据,支持抑郁症与痔疮疾病之间的双向因果关系。
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引用次数: 0
A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis. 对非洲大陆祖先群体中性粒细胞数量的全基因组关联研究有助于疟疾发病机制的研究。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-15 DOI: 10.1186/s40246-024-00585-w
Andrei-Emil Constantinescu, David A Hughes, Caroline J Bull, Kathryn Fleming, Ruth E Mitchell, Jie Zheng, Siddhartha Kar, Nicholas J Timpson, Borko Amulic, Emma E Vincent

Background: 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056).

Results: We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null.

Conclusion: Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

背景:"良性种族中性粒细胞减少症"(BEN)是一种遗传性疾病,其特点是中性粒细胞计数较低,主要见于非洲血统的个体,而 BEN 的遗传基础仍是一个广泛研究的课题。在本研究中,我们旨在通过线性混合模型全基因组关联研究(GWAS),在非洲血统人群(N = 5976)中剖析中性粒细胞计数变异的遗传结构。由恶性疟原虫引起的疟疾给撒哈拉以南非洲地区的居民带来了巨大的公共卫生负担。生活在疟疾流行地区的人通常会因 BEN 而导致循环中性粒细胞数量减少,这就提出了一种可能性,即中性粒细胞数量的减少会调节易感人群中疟疾的严重程度。作为后续研究,我们对中性粒细胞计数对重症疟疾的影响进行了孟德尔随机分析(MR),从而验证了这一假设(MalariaGEN,N = 17,056):我们对英国生物库中与非洲大陆血统组相关的个体的中性粒细胞计数进行了GWAS分析,确定了与中性粒细胞计数相关的73个位点(r2 = 0.1)和10个指数SNPs(GCTA-COJO位点),其中包括之前未知的在非欧洲人群中调节中性粒细胞计数的罕见位点。在非欧洲人群中进行 BOLT-LMM 分析是可靠的,模型中添加的其他协变量在很大程度上不会改变顶级位点或指数 SNP 的结果。中性粒细胞计数与严重疟疾之间的双向MR分析显示,中性粒细胞计数与严重贫血之间的效应证据最多,但置信区间越过了空值:我们的中性粒细胞计数基因组学分析揭示了存在于非洲血统个体中的独特基因位点。我们注意到,在我们的 GWAS 中,小样本量降低了我们识别低等位基因频率和/或低效应大小变异的能力。我们的工作强调了在非洲开展大规模生物库研究以及进一步探索中性粒细胞与重症疟疾之间联系的必要性。
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引用次数: 0
Statistical methods for assessing the effects of de novo variants on birth defects 评估新生变异对出生缺陷影响的统计方法
IF 4.5 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-03-14 DOI: 10.1186/s40246-024-00590-z
Yuhan Xie, Ruoxuan Wu, Hongyu Li, Weilai Dong, Geyu Zhou, Hongyu Zhao
With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing samples and the low occurrence of DNVs. DNV analysis is further complicated by genetic heterogeneity across diseased individuals. Therefore, it is critical to jointly analyze DNVs with other types of genomic/biological information to improve statistical power to identify genes associated with birth defects. In this review, we discuss the general workflow, recent developments in statistical methods, and future directions for DNV analysis.
随着下一代测序技术的发展,具有有害影响的新生变异(DNVs)可以被识别出来,并研究它们对先天性心脏病(CHD)等出生缺陷的影响。然而,由于招募和测序样本的成本较高,样本量较小,且 DNV 的发生率较低,因此此类研究的统计能力仍然有限。患病个体间的遗传异质性使 DNV 分析变得更加复杂。因此,将 DNV 与其他类型的基因组/生物学信息联合分析,以提高识别出生缺陷相关基因的统计能力至关重要。在这篇综述中,我们将讨论 DNV 分析的一般工作流程、统计方法的最新进展和未来方向。
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引用次数: 0
Cellular and clinical impact of protein phosphatase enzyme epigenetic silencing in multiple cancer tissues. 多种癌症组织中蛋白磷酸酶表观遗传沉默对细胞和临床的影响。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-12 DOI: 10.1186/s40246-024-00592-x
Edward Wiltshire, Manuel Castro de Moura, David Piñeyro, Ricky S Joshi

Background: Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signalling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations.

Methods: In this study, we examined promoter-associated DNA methylation profiles in Protein Phosphatase Enzymes and their Interacting Proteins (PPEIP) in a cohort of 705 cancer patients in five tissues (Large intestine, Oesophagus, Lung, Pancreas and Stomach) in three cell models (primary tumours, cancer cell lines and 3D embedded cancer cell cultures). As a subset of PPEIP are known tumour suppressor genes, we analysed the impact of PPEIP promoter hypermethylation marks on gene expression, cellular networks and in a clinical setting.

Results: Here, we report epimutations in PPEIP are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumours have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity.

Conclusions: We propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and within the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.

背景:蛋白磷酸酶(PPE)和蛋白激酶同时控制着磷酸化机制,而磷酸化机制可严格调节细胞内信号通路并刺激细胞反应。在人类恶性肿瘤中,蛋白磷酸酶和蛋白激酶经常发生突变,导致激酶活性失控和蛋白磷酸酶抑制,从而导致细胞增殖、迁移和对抗癌疗法产生抗药性。与癌症相关的 PPE 启动子 DNA 高甲基化会导致转录沉默(表突变),这是癌症的一大特征。尽管最近在测序技术、数据可用性和计算能力方面取得了进展,但只有一小部分 PPE 因表型突变而转录失活:在这项研究中,我们通过三种细胞模型(原发性肿瘤、癌细胞系和三维嵌入式癌细胞培养物)检测了705名癌症患者的五种组织(大肠、食道、肺、胰腺和胃)中蛋白磷酸酶酶及其相互作用蛋白(PPEIP)的启动子相关DNA甲基化图谱。由于 PPEIP 的一部分是已知的肿瘤抑制基因,我们分析了 PPEIP 启动子高甲基化标记对基因表达、细胞网络和临床环境的影响:结果:在此,我们报告了 PPEIP 的表突变在癌症基因组中的频繁发生,其表现与转录活性无关。我们观察到不同肿瘤对表观突变的易感性不同,并确定了主要受表观突变影响的特定细胞信号网络。此外,RNA-seq分析显示表观突变对大多数(而非全部)蛋白酪氨酸磷酸酶转录有负面影响。最后,我们发现了一些新的临床生物标志物,这些标志物可为患者死亡率和抗癌治疗敏感性提供信息:我们认为,PPEIP 上的 DNA 高甲基化标记经常导致恶性肿瘤的发病机制,在精准医疗领域,它有望作为生物标志物,为患者生存和治疗反应等临床特征提供信息。
{"title":"Cellular and clinical impact of protein phosphatase enzyme epigenetic silencing in multiple cancer tissues.","authors":"Edward Wiltshire, Manuel Castro de Moura, David Piñeyro, Ricky S Joshi","doi":"10.1186/s40246-024-00592-x","DOIUrl":"10.1186/s40246-024-00592-x","url":null,"abstract":"<p><strong>Background: </strong>Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signalling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations.</p><p><strong>Methods: </strong>In this study, we examined promoter-associated DNA methylation profiles in Protein Phosphatase Enzymes and their Interacting Proteins (PPEIP) in a cohort of 705 cancer patients in five tissues (Large intestine, Oesophagus, Lung, Pancreas and Stomach) in three cell models (primary tumours, cancer cell lines and 3D embedded cancer cell cultures). As a subset of PPEIP are known tumour suppressor genes, we analysed the impact of PPEIP promoter hypermethylation marks on gene expression, cellular networks and in a clinical setting.</p><p><strong>Results: </strong>Here, we report epimutations in PPEIP are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumours have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity.</p><p><strong>Conclusions: </strong>We propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and within the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10935810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Zebrafish as a model to investigate a biallelic gain-of-function variant in MSGN1, associated with a novel skeletal dysplasia syndrome 以斑马鱼为模型,研究与新型骨骼发育不良综合征有关的 MSGN1 双重功能增益变体
IF 4.5 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-03-06 DOI: 10.1186/s40246-024-00593-w
Asuman Koparir, Caroline Lekszas, Kemal Keseroglu, Thalia Rose, Lena Rappl, Aboulfazl Rad, Reza Maroofian, Nakul Narendran, Atefeh Hasanzadeh, Ehsan Ghayoor Karimiani, Felix Boschann, Uwe Kornak, Eva Klopocki, Ertuğrul M. Özbudak, Barbara Vona, Thomas Haaf, Daniel Liedtke
Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix–Loop–Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.
导致特定先天性发育异常的罕见遗传病通常在单个家族中出现。尽管这些调查可能为患者提供新的治疗方案,但大多数情况下缺乏对致病分子特征的调查。在这项研究中,我们旨在确定一名伊朗严重骨骼发育不良患者的遗传病因,并在斑马鱼胚胎中模拟其分子功能。该患者身材矮小,骨骼发育异常,包括双臂中胚层发育不良,肱骨-桡骨-乌骨完全突节,锁骨拱起,骨盆发育不良,腓骨短而薄,脊椎骨比例性短,脊柱过度弯曲和轻度后凸。该患者的外显子组测序结果显示,MSGN1(NM_001105569)存在一个新的同源c.374G > T, p.(Arg125Leu) 错义变异。MSGN1是一种碱性-elix-Loop-Helix转录因子,在脊椎动物早期发育过程中对绒毛膜前中胚层祖细胞/中胚层干细胞的形成起着至关重要的作用。初步的体外实验表明,这种新型变体具有蛋白质稳定性,并能在细胞核内正确定位,这意味着其转录因子功能得以保留。为了检验检测到的变体的致病性,我们在斑马鱼胚胎中过表达了野生型和突变型 msgn1 mRNA,并对 tbxta(T/brachyury/ntl)进行了分析。与对照胚胎相比,过表达野生型或突变型msgn1 mRNA会显著减少尾芽中tbxta的表达。注入突变体 msgn1 mRNA 的胚胎受到的影响更为严重,这意味着存在功能增益机制。通过在斑马鱼胚胎中克隆过表达 msgn1,对胚胎发育进行了体内分析,进一步证实了绒毛前中胚层、脊索和胸鳍芽的细胞区发生了改变。在这些胚胎中检测到 tbx6 和 bmp2 的异位表达,表明 Msgn1 功能缺失导致下游信号受到影响。与动物基因敲除模型中描述的功能缺失效应不同,MSGN1 的功能增益可以解释为什么该原虫的轴向骨骼仅受到轻微影响,而脊椎骨却相当正常。在这种情况下,我们观察到斑马鱼胚胎过表达 msgn1 后,脊索弯曲,胸鳍芽/上肢可能受到破坏。后者可能是由于Msgn1对这些区域的间充质干细胞或软骨生成起了作用。此外,我们还在斑马鱼中检测到了Msgn1功能获得后tbx6和bmp2a的异位表达,这与患者的身材矮小、先天性脊柱侧弯、肢体短小和突出的骨骼畸形有关。我们的发现突显了一种罕见的、迄今尚未描述过的骨骼发育不良综合征,它与 MSGN1 的功能增益突变有关,并提示了其分子下游效应因子。
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引用次数: 0
Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy. TSPAN12 基因突变导致家族性渗出性玻璃体视网膜病变。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-03-01 DOI: 10.1186/s40246-024-00589-6
Yuqiao Ju, Tianhui Chen, Lu Ruan, Ye Zhao, Qing Chang, Xin Huang

Background: To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR.

Results: Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors.

Conclusions: Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.

背景:报告新发现的TSPAN12突变与一种独特形式的家族性渗出性玻璃体视网膜病变(FEVR),并找出TSPAN12中重复出现的新型内含子变异导致FEVR的可能机制:结果:通过基于面板的 NGS 检测发现了九个 TSPAN12 突变,这些突变具有 FEVR 的独特形式。MINI-Gene 检测显示 mRNA 有两种剪接模式,分别处理 A 和 B 两条不同的带,突变型显示出 Exon11 跳接的剪接模式。在构建野生型和突变型 TSPAN12 载体时,发现出现了过早终止密码子(PTC)。体外表达检测显示,与野生型相比,转染突变型载体的细胞中 TSPAN12 mRNA 和蛋白质的表达水平明显下调。相反,翻译抑制剂CHX和UPF1小干扰RNA(si-UPF1)能显著提高转染突变载体的细胞中TSPAN12 mRNA或蛋白的表达量:在9例FEVR患者中,TSPAN12基因出现了9个突变,并伴有一系列独特的眼部异常。三例新型 TSPAN12 基因突变引发的 NMD 将导致参与微纤维生物合成和组装的 TSPAN12 蛋白减少,从而可能导致 FEVR,并提示内含子序列分析可能是遗传咨询和产前诊断的重要工具。
{"title":"Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy.","authors":"Yuqiao Ju, Tianhui Chen, Lu Ruan, Ye Zhao, Qing Chang, Xin Huang","doi":"10.1186/s40246-024-00589-6","DOIUrl":"10.1186/s40246-024-00589-6","url":null,"abstract":"<p><strong>Background: </strong>To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR.</p><p><strong>Results: </strong>Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors.</p><p><strong>Conclusions: </strong>Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Human Genomics
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