Research Papers
Allele frequency impacts the cross-ancestry portability of gene expression prediction in lymphoblastoid cell lines
等位基因频率影响淋巴细胞系中基因表达预测的跨族裔可移植性
Authors: Saitou, Marie, Dahl, Andy, Wang, Qingbo, Liu, Xuanyao
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.009
Abstract
Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of prediction accuracy across ancestries. In this study, we used gene expression levels in lymphoblastoid cell lines to understand how much each genetic factor contributes to lowered portability of gene expression prediction from European to African ancestries. We found that cis-genetic effects on gene expression are highly similar between European and African individuals. However, we found that allele frequency differences of causal variants have a striking impact on prediction portability. For example, portability is reduced by more than 32% when the causal cis-variant is common (minor allele frequency, MAF >5%) in European samples (training population) but is rarer (MAF <5%) in African samples (prediction population). While large allele frequency differences can decrease portability through increasing LD differences, we also determined that causal allele frequency can significantly impact portability when the impact from LD is substantially controlled. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability resulting from differences in causal allele frequency. We conclude that causal cis-eQTL effects are highly similar in European and African individuals, and allele frequency differences have a large impact on the accuracy of gene expression prediction.
摘要
群体水平的遗传研究在很大程度上偏向于欧洲人群。将欧洲人群的遗传预测转移到其他人群会导致准确性的显著下降。然而，目前尚不清楚各种遗传因素，如因果效应差异、连锁不平衡（LD）差异或等位基因频率差异，对跨族裔预测准确性损失的贡献程度。在本研究中，我们使用淋巴细胞系的基因表达水平来了解每个遗传因素对基因表达预测从欧洲人群到非洲人群可移植性降低的贡献程度。我们发现，顺式遗传效应对基因表达的影响在欧洲和非洲个体之间高度相似。然而，我们发现因果变异的等位基因频率差异对预测可移植性有显著影响。例如，当因果顺式变异在欧洲样本（训练群体）中常见（次等位基因频率，MAF >5%），但在非洲样本（预测群体）中较罕见（MAF <5%）时，可移植性降低超过32%。虽然较大的等位基因频率差异可能通过增加LD差异来降低可移植性，但我们还确定，当LD的影响被大幅控制时，因果等位基因频率仍能显著影响可移植性。这一观察结果表明，仅仅改进统计精细定位并不能克服由因果等位基因频率差异导致的可移植性损失。我们得出结论，因果顺式表达数量性状位点（eQTL）效应在欧洲和非洲个体之间高度相似，而等位基因频率差异对基因表达预测的准确性有很大影响。
Local genetic correlation via knockoffs reduces confounding due to cross-trait assortative mating
通过敲除法减少跨性状同配婚姻导致的局部遗传相关性混淆
Authors: Ma, Shiyang, Wang, Fan, Border, Richard, Buxbaum, Joseph, Zaitlen, Noah, Ionita-Laza, Iuliana
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.012
Abstract
Local genetic correlation analysis is an important tool for identifying genetic loci with shared biology across traits. Recently, Border et al. have shown that the results of these analyses are confounded by cross-trait assortative mating (xAM), leading to many false-positive findings. Here, we describe LAVA-Knock, a local genetic correlation method that builds off an existing genetic correlation method, LAVA, and augments it by generating synthetic data in a way that preserves local and long-range linkage disequilibrium (LD), allowing us to reduce the confounding induced by xAM. We show in simulations based on a realistic xAM model and in genome-wide association study (GWAS) applications for 630 trait pairs that LAVA-Knock can greatly reduce the bias due to xAM relative to LAVA. Furthermore, we show a significant positive correlation between the reduction in local genetic correlations and estimates in the literature of cross-mate phenotype correlations; in particular, pairs of traits that are known to have high cross-mate phenotype correlation values have a significantly higher reduction in the number of local genetic correlations compared with other trait pairs. A few representative examples include education and intelligence, education and alcohol consumption, and attention-deficit hyperactivity disorder and depression. These results suggest that LAVA-Knock can reduce confounding due to both short-range LD and long-range LD induced by xAM.
摘要
局部遗传相关性分析是识别跨性状共享生物学的遗传位点的重要工具。最近，Border等人表明，这些分析的结果受到跨性状同配婚姻（xAM）的混淆，导致许多假阳性发现。在此，我们描述了LAVA-Knock，一种局部遗传相关性方法，它基于现有的遗传相关性方法LAVA，并通过以保留局部和长程连锁不平衡（LD）的方式生成合成数据来增强它，从而允许我们减少xAM引起的混淆。我们在基于现实xAM模型的模拟和630对性状的全基因组关联研究（GWAS）应用中显示，相对于LAVA，LAVA-Knock可以大大减少由xAM引起的偏差。此外，我们发现局部遗传相关性的减少与文献中报道的跨配偶表型相关性估计之间存在显著的正相关；特别是，已知具有高跨配偶表型相关值的性状对与其他性状对相比，局部遗传相关性数量的减少显著更高。一些代表性的例子包括教育和智力、教育和酒精消费、注意力缺陷多动障碍和抑郁症。这些结果表明，LAVA-Knock可以减少由短程LD和xAM引起的长程LD导致的混淆。
Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome
蛋白质组范围的孟德尔随机化和功能研究揭示多囊卵巢综合征的治疗靶点
Authors: Ni, Feida, Wang, Feixia, Sun, Jing, Tu, Mixue, Chen, Jianpeng, Shen, Xiling, Ye, Xiaohang, Chen, Ruixue, et al.
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.008
Abstract
Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization analyses were performed to prioritize the causal role of candidate proteins. Protein-protein interaction (PPI) and druggability evaluation assessed the druggability of candidate proteins. We evaluated the enrichment of tier 1 and 2 candidate proteins in individuals with PCOS and a mouse model and explored the potential application of the identified drug target. Genetically predicted levels of 65 proteins exhibited associations with PCOS risk, with 30 proteins showing elevated levels and 35 proteins showing decreased levels linked to higher susceptibility. PPI analyses revealed that FSHB, POSTN, CCN2, and CXCL11 interacted with targets of current PCOS medications. Eighty medications targeting 20 proteins showed their potential for repurposing as therapeutic targets for PCOS. EGLN1 levels were elevated in granulosa cells and the plasma of individuals with PCOS and in the plasma and ovaries of dehydroepiandrosterone (DHEA)-induced PCOS mouse model. As an EGLN1 inhibitor, administration of roxadustat in the PCOS mouse model elucidated the EGLN1-HIF1α-ferroptosis axis in inducing PCOS and validated its therapeutic effect in PCOS. Our study identifies candidate proteins causally associated with PCOS risk and suggests that targeting EGLN1 provides a promising treatment strategy.
摘要
多囊卵巢综合征（PCOS）是一种影响全球大量女性的内分泌综合征。本蛋白质基因组学和功能研究旨在发现PCOS的候选治疗靶点。我们使用双样本孟德尔随机化分析全面调查了循环蛋白质与PCOS之间的因果关联。顺式蛋白质数量性状位点来自六项关于血浆蛋白质组的全基因组关联研究（GWAS）。PCOS的遗传关联来自大规模GWAS荟萃分析、FinnGen队列和英国生物银行。进行共定位分析以优先确定候选蛋白质的因果作用。蛋白质-蛋白质相互作用（PPI）和可药性评估评估了候选蛋白质的可药性。我们评估了PCOS患者和小鼠模型中一级和二级候选蛋白质的富集情况，并探讨了已识别药物靶点的潜在应用。65种蛋白质的遗传预测水平与PCOS风险相关，其中30种蛋白质水平升高，35种蛋白质水平降低与更高的易感性相关。PPI分析显示FSHB、POSTN、CCN2和CXCL11与当前PCOS药物的靶点相互作用。针对20种蛋白质的80种药物显示出作为PCOS治疗靶点的重新定位潜力。EGLN1水平在PCOS患者的颗粒细胞和血浆中以及脱氢表雄酮（DHEA）诱导的PCOS小鼠模型的血浆和卵巢中升高。作为EGLN1抑制剂，在PCOS小鼠模型中给予罗沙司他阐明了EGLN1-HIF1α-铁死亡轴在诱导PCOS中的作用，并验证了其在PCOS中的治疗效果。我们的研究确定了与PCOS风险因果相关的候选蛋白质，并表明靶向EGLN1提供了一种有前景的治疗策略。
Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly
利用长读序列和端到端组装解析环状染色体、罗伯逊易位和复杂结构变异
Authors: Mostovoy, Yulia, Boone, Philip M., Huang, Yongqing, Garimella, Kiran V., Tan, Kar-Tong, Russell, Bianca E., Salani, Monica, de Esch, Celine E.F., et al.
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.006
Abstract
Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.
摘要
在高度重复的基因组区域中以序列分辨率描述结构变异（SVs）长期以来一直是一个难题。诸如环状染色体和罗伯逊易位等类型的基因组重排的序列特性、起源和功能效应仍然未知。为了解析这些复杂结构，我们利用了该领域最近的几个里程碑，包括：（1）长读序列技术的出现，（2）无间隙的端到端（T2T）组装，以及（3）一种从长读序列中发现染色体重排的工具（BigClipper）。我们将这些技术应用于13个短读无法解析的环状染色体、罗伯逊易位和复杂SV案例，并通过光学基因组图谱（OGM）进行验证。我们的分析解析了13个案例中的10个，包括一个罗伯逊易位和所有环状染色体。多个断点被定位到先前难以测序的基因组区域，如近端着丝粒短臂、核糖体DNA阵列和端粒重复序列，并涉及复杂结构，如缺失-倒位和染色体间分散重复。我们还从长读数据中进行甲基化分析，发现了环融合附近基因启动子的相位差异甲基化，表明存在异染色质扩散的长程位置效应（LRPE）。断点序列提示了SV形成的机制，如微同源介导和非同源末端连接，以及非等位同源重组。这些方法首次提供了罗伯逊易位的序列分辨率，并揭示了环状染色体和复杂染色体重排的结构多样性，对基因组生物学、利用集成多组学技术预测LRPE以及罕见疾病案例的分子诊断具有重要意义。
GPS-Net: Discovering prognostic pathway modules based on network regularized kernel learning
GPS-Net：基于网络正则化核学习发现预后通路模块
Authors: Yao, Sijie, Li, Kaiqiao, Li, Tingyi, Yu, Xiaoqing, Kuan, Pei Fen, Wang, Xuefeng
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.004
Abstract
The search for prognostic biomarkers capable of predicting patient outcomes, by analyzing gene expression in tissue samples and other molecular profiles, remains largely focused on single-gene-based or global-gene-search approaches. Gene-centric approaches, while foundational, fail to capture the higher-order dependencies that reflect the activities of co-regulated processes, pathway alterations, and regulatory networks, all of which are crucial in determining the patient outcomes in complex diseases like cancer. Here, we introduce GPS-Net, a computational framework that fills the gap in efficiently identifying prognostic modules by incorporating the holistic pathway structures and the network of gene interactions. By innovatively incorporating advanced multiple kernel learning techniques and network-based regularization, the proposed method not only enhances the accuracy of biomarker and pathway identification but also significantly reduces computational complexity, as demonstrated by extensive simulation studies. Applying GPS-Net, we identified key pathways that are predictive of patient outcomes in a cancer immunotherapy study. Overall, our approach provides a novel framework that renders genome-wide pathway-level prognostic analysis both feasible and scalable, synergizing both mechanism-driven and data-driven methodologies for precision genomics.
摘要
通过分析组织样本中的基因表达和其他分子特征来寻找能够预测患者预后的生物标志物的研究，目前仍主要集中在单基因或全基因搜索方法上。以基因为中心的方法虽然具有基础性，但无法捕捉反映共同调控过程、通路改变和调控网络活动的高阶依赖关系，而这些在癌症等复杂疾病中对患者预后至关重要。在此，我们提出了GPS-Net，这是一个计算框架，通过整合整体通路结构和基因相互作用网络，有效地识别预后模块，填补了这一研究空白。通过创新性地结合先进的多核学习技术和基于网络的正则化，该方法不仅提高了生物标志物和通路识别的准确性，还显著降低了计算复杂度，这一点在广泛的模拟研究中得到了证实。应用GPS-Net，我们在一项癌症免疫治疗研究中识别出了能预测患者预后的关键通路。总的来说，我们的方法提供了一个新颖的框架，使全基因组水平的通路预后分析变得可行且可扩展，为精准基因组学研究协同了机制驱动和数据驱动的方法。
Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions
匹配的正常和肿瘤乳腺组织的基因组和表观基因组揭示多样化的进化轨迹和肿瘤-宿主相互作用
Authors: Zhu, Bin, Tapinos, Avraam, Koka, Hela, Yi Lee, Priscilla Ming, Zhang, Tongwu, Zhu, Wei, Wang, Xiaoyu, Klein, Alyssa, et al.
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.005
Abstract
Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors.
摘要
邻近肿瘤的正常组织（NATs）可能存在由癌症场效应驱动的早期乳腺癌发生事件。尽管先前的研究已经描述了拷贝数（CN）和转录组的改变，但乳腺癌（BC）中NATs的进化历史仍然不清楚。利用全基因组测序（WGS）、甲基化分析和RNA测序（RNA-seq），我们分析了来自香港43名乳腺癌患者的配对生殖细胞、NATs和肿瘤样本。我们发现单核苷酸变异（SNVs）在NATs中很常见，三分之一的NAT样本在驱动基因中表现出SNVs，其中许多也存在于配对的肿瘤样本中。肿瘤和NAT样本中最常见的突变基因是PIK3CA、TP53、GATA3和AKT1。相比之下，大规模的异常如体细胞拷贝数改变（SCNAs）和结构变异（SVs）在NAT样本中很少被检测到。我们生成了系统发生树来研究配对NAT和肿瘤样本的进化历史。它们可以分为仅肿瘤、共享和多树组，其中最后一组与非遗传性癌症场效应一致。这些组在NAT和肿瘤样本中都表现出不同的基因组和表观基因组特征。具体而言，共享树组中的NAT样本显示出更高的突变数量，而属于多树组的NAT样本显示出较少的炎症性肿瘤微环境（TME），特征是调节性T细胞（Tregs）比例较高和CD14细胞群体较少。总之，我们的发现强调了乳腺癌NAT/肿瘤配对中多样化的进化历史，以及癌症场效应和TME在塑造肿瘤基因组进化历史中的影响。
3D genome topology distinguishes molecular subgroups of medulloblastoma
三维基因组拓扑结构区分髓母细胞瘤的分子亚型
Authors: Lee, John J.Y., Johnston, Michael J., Farooq, Hamza, Chen, Huey-Miin, Younes, Subhi Talal, Suarez, Raul, Zwaig, Melissa, Juretic, Nikoleta, et al.
Journal: The American Journal of Human Genetics
DOI: 10.1016/j.ajhg.2024.10.003
Abstract
Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD insulation score differences between subtypes were globally not associated with differential gene expression, although we identified few exceptions near genes expressed in the lineages of origin of specific MB subtypes. Our study therefore supports the notion that TAD insulation scores can distinguish MB subtypes independently of their transcriptional differences.
摘要
基于转录、DNA甲基化和遗传谱，已经确定了四种主要的髓母细胞瘤（MB）分子亚型。然而，目前尚不清楚3D基因组结构是否在MB亚型之间存在差异。为解答这个问题，我们进行了原位Hi-C实验以重建MB亚型的3D基因组结构。总共，我们为28个手术标本生成了Hi-C和匹配的转录组数据，并为一个患者衍生的异种移植物生成了Hi-C数据。Hi-C图谱的平均分辨率为6,833碱基对。利用这些数据，我们发现拓扑相关结构域（TADs）的绝缘评分能有效区分MB分子亚型。亚型间TAD绝缘评分的差异在全局上与基因表达差异无关，尽管我们在特定MB亚型起源谱系表达的基因附近发现了少数例外。因此，我们的研究支持TAD绝缘评分可以独立于转录差异来区分MB亚型的观点。
The “Genetic Test Request”: A genomic stewardship intervention for inpatient exome and genome orders at a tertiary pediatric hospital
"基因检测申请"：一项针对三级儿童医院住院患者外显子组和基因组检测订单的基因组管理干预
Authors: Saba, Lisa F., Streff, Haley, Lopez-Terrada, Dolores, Scull, Jennifer
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101330
Abstract
Purpose:Exome and genome sequencing (ES, GS) are useful tests to diagnose rare disease in pediatric patients in critical care settings. Genomic test stewardship can increase appropriate use of these tests leading to improved diagnostics and cost savings.Methods:Mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics.Results:There were 444 Genetic Test Request (GTR) orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval leading to an overall cost savings of $345,821.00 USD or $778 USD per order. The combined diagnostic rate was 28.2% in this patient population.Conclusion:Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.
摘要
目的：外显子组和基因组测序（ES、GS）是在重症护理环境中诊断儿科患者罕见疾病的有用检测。基因组检测管理可以增加这些检测的适当使用，从而改善诊断并节省成本。方法：2023年3月开始实施对住院患者ES和GS订单的强制审查。使用描述性统计分析了截至2024年2月的审查结果、成本分析和后续检测结果。结果：共有412名独立患者提交了444份基因检测申请（GTR）订单。其中，81份（18.2%）被重新定向，57份（12.8%）在批准后需要修改，总体节省成本345,821.00美元，即每份订单节省778美元。该患者群体的综合诊断率为28.2%。结论：对儿科住院患者ES/GS订单的管理是改善这些基因组检测适当使用的有效工具。与利益相关者的进一步合作和扩大基因组管理举措可能会缩短危重儿科患者的诊断过程，并实现成本节省。
Payer Perspectives on Genomic Testing in the United States: A systematic literature review
美国支付方对基因组测试的看法：系统文献综述
Authors: Wiedower, Julie, Smith, Hadley Stevens, Farrell, Christopher L., Parker, Veronica, Rebek, Laura, Davis, Stephanie Clark
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101329
Abstract
Purpose:Healthcare stakeholders' perspectives on the value of genomic testing vary widely and directly impact the access and practice of genomic medicine. A review of United States healthcare payers' perspectives on genomic testing has not been performed.Methods:We conducted a systematic literature review of US payers' perspectives on genomic testing in the MEDLINE, PubMed and CINAHL databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records and using the framework method, common domains were recorded.Results:Domains included clinical utility, coverage decision frameworks, potential harms, costs, "paying for research," demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous.Conclusion:A deeper understanding of how payers approach genomic testing may allow comparison to other stakeholders' perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.
摘要
目的：医疗保健利益相关者对基因组测试价值的看法差异很大，这直接影响了基因组医学的获取和实践。目前尚未对美国医疗保健支付方对基因组测试的看法进行综述。方法：我们在MEDLINE、PubMed和CINAHL数据库中对美国支付方对基因组测试的看法进行了系统文献综述。在筛选的161条非重复记录中，我们总结了20条包含的记录的发现，并使用框架方法记录了常见领域。结果：涉及的领域包括临床实用性、覆盖决策框架、潜在危害、成本、"为研究付费"、需求/压力、考虑结果的灵活性和个人实用性。对临床实用性的定义达成共识，即改善健康结果，并报告称基因组测试的细微差别难以适应现有的覆盖决策框架。对于接受更广泛的基因组测试结果或用途以及成本是否影响覆盖决策的看法各不相同。研究方法学存在异质性。结论：深入了解支付方如何处理基因组测试可能有助于与其他利益相关者的观点进行比较，并可能识别挑战、机会和解决方案，以更好地调整概念和证据框架，以展示基因组测试的价值。
Offering complex genomic screening in acute pediatric settings: family decision-making and outcomes
在急诊儿科环境中提供复杂基因组筛查：家庭决策和结果
Authors: Martyn, Melissa, Lee, Ling, Jan, Alli, Tytherleigh, Rigan, Lynch, Fiona, Mighton, Chloe, Bouffler, Sophie E., Lynch, Elly, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101327
Abstract
Purpose:Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences.Methods:A cohort of 235 families who had completed ultrarapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to 3 screens on their genomic data: pediatric-onset, adult-onset, and expanded couple carrier screening. We investigated decision making, understanding, and service delivery preferences using surveys at 3 time points (pre counseling, post counseling, and post result) and performed inductive content analysis of pretest genetic counseling transcripts.Results:A total of 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening easy (87%) compared with adult (68%; P = .002) or pediatric (71%; P = .01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this 1 month later. A delayed offer of screening was acceptable to most respondents (78%).Conclusion:Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely.
摘要
目的：在儿科急诊中接受超快速基因组测序的儿童家庭在高压时期做出复杂决定。为了减少家庭和临床医生的复杂性，我们在完成诊断测试后为儿童和父母提供基因组筛查。我们评估了接受度、理解程度和服务提供偏好。方法：在17家澳大利亚医院完成超快速诊断基因组测序的235个家庭被提供最多3种基因组数据筛查：儿童发病、成人发病和扩展夫妇携带者筛查。我们通过3个时间点（咨询前、咨询后和结果后）的调查研究了决策、理解和服务提供偏好，并对遗传咨询前转录本进行了归纳内容分析。结果：共有119个家庭（51%）参加了遗传咨询，其中115个（49%）接受了基因组筛查。与成人（68%；P = .002）或儿童（71%；P = .01）筛查决定相比，调查受访者更容易做出夫妇携带者筛查的决定（87%）。所有检测到新的致病变异的受访者在一个月后都能准确回忆起这一点。大多数受访者（78%）可以接受延迟提供筛查。结论：将基因组筛查与压力较大的诊断期分开得到了家庭的支持，他们表现出良好的知识和回忆能力。我们的结果表明，应该在更广泛的范围内尝试延迟基因组筛查。
Upregulation vs. loss of function of NTRK2 in 44 affected individuals leads to two distinct neurodevelopmental disorders
NTRK2上调与功能丧失在44名受影响个体中导致两种不同的神经发育障碍
Authors: Berger, Eva, Jauss, Robin-Tobias, Ranells, Judith D., Zonic, Emir, von Wintzingerode, Lydia, Wilson, Ashley, Wagner, Johannes, Tuttle, Annabelle, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101326
Abstract
Introduction:Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation METHODS: We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported.Results:Our analysis led to splitting the cohort into two entities.Discussion:One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia.
摘要
引言：NTRK2（HGNC：8032）的杂合致病变异与全面发育迟缓有关。然而，目前仅在小型或一般研究中描述了零星病例。我们的工作旨在巩固对NTRK2相关疾病的理解，并描述其临床表现。方法：我们报告了44名受影响个体的扩展队列，其中19名来自文献，25名为此前未报告的病例。结果：我们的分析将队列分为两个实体。讨论：一组在跨膜域的胆固醇结合基序中存在变异，其中大多数是重复出现的变异c.1301A>G p.(Tyr434Cys)。这些变异可能导致TRKB活性上调，并引起严重的表型，包括发育迟缓/智力障碍、肌肉张力低下、难治性癫痫、视觉障碍和失明以及进食困难。第二组具有截断变异或可能扰乱蛋白质3D结构导致功能丧失的变异。这些个体表现出明显较轻的表型，包括发育迟缓、肥胖和多食。
Response to Connolly et al.
对Connolly等人的回应
Authors: Houtz, Cassie
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101325
Abstract
No Abstract
摘要
无摘要
Opportunistic genomic screening has clinical utility: An interventional cohort study
机会性基因组筛查具有临床实用性：一项干预性队列研究
Authors: Mighton, Chloe, Kodida, Rita, Shickh, Salma, Clausen, Marc, Reble, Emma, Sam, Jordan, Grewal, Sonya, Hirjikaka, Daena, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101323
Abstract
Background:Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants' clinical features and family history.Methods:Adult cancer patients had GS with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.Results:All participants (n=139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the ACMG list (v3.2, non-cancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.Conclusions:Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.
摘要
背景：实践正在向基因组优先的方法转变，如机会性筛查次要发现（SFs）。SFs的分析可以从医学上可采取行动的结果扩展到包括非医学上可采取行动的单基因疾病风险、携带者状态、药物基因组变异和常见复杂疾病的风险变异。然而，关于返回这些结果的临床实用性的证据还很缺乏。我们通过评估产出、对临床管理的影响以及SFs与参与者临床特征和家族史之间的一致性，评估了广泛SFs机会性筛查的结果。方法：成年癌症患者进行了基因组测序（GS），并可选择了解多类SFs。通过病历审查和参与者报告的措施，收集了结果返回后长达一年的结果数据。结果：所有选择了解SFs的参与者（n=139，85.6%为女性，平均54.6岁）都报告了≥1个变异（100% [139/139]）。可报告发现的产出率最高的是药物基因组变异（97.8% [135/138]的参与者），其次是常见疾病风险变异（89.4% [118/132]），携带者状态（89.3% [117/131]），以及与孟德尔遗传（27.2% [34/125]）、医学上可采取行动（15.2% [21/138]）和早发性神经退行性（2.6% [3/117]）疾病风险相关的变异。ACMG列表（v3.2，非癌症基因）中的SFs在1.4%（2/138）的参与者中被报告。所有类别的SFs都显示了临床实用性，促使28.1%（39/139）的参与者改变了管理方式。此外，相当比例的参与者具有可能与其SFs相关的提示性临床特征（49.0%[24/49]）或家族史（21.8%[27/124]）。结论：我们的发现表明，对广泛SFs进行机会性筛查可能具有潜在益处。
Correspondence on "Weighty matters: Considering the ethics of genetic risk scores for obesity" by C. Houtz
关于C. Houtz的"重要问题：考虑肥胖遗传风险评分的伦理"的通信
Authors: Connolly, John J., Hess, Molly, Maripuri, Priyanka, Terek, Shannon, Purcell, Jasmine, Harr, Margaret, Mentch, Frank D., Glessner, Joseph T., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101324
Abstract
No Abstract
摘要
无摘要
Micro-costing genomics: Challenges and opportunities
基因组学微成本计算：挑战与机遇
Authors: Santos-Gonzalez, Francisco, Ungar, Wendy J., Buchanan, James, Christodoulou, John, Stark, Zornitza, Goranitis, Ilias
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101310
Abstract
Understanding the economic cost of genomic sequencing is important for appropriately informing prioritization and reimbursement decisions. Microcosting is a way of estimating the economic cost of genomic sequencing by identifying, measuring, and valuing the resources required for its intended delivery. Genomic sequencing is a complex multistep molecular diagnostic test, which entails end-to-end workflow mapping, ranging from sample reception, library processing, sequencing, and data processing to interpretation and reporting which involves labor, bioinformatics, equipment, consumables, and overhead costs. Although there has been a number of microcosting studies of genomic sequencing,3 the lack of detailed cost estimates has led to misleading claims about falling costs and mischaracterizations of costs, and has been a well-documented limitation in health economic evaluations,2,6 which commonly incorporate laboratory charges instead of resource cost estimates of genomic sequencing.
摘要
了解基因组测序的经济成本对于适当地为优先级和报销决策提供信息非常重要。微成本计算是一种通过识别、测量和评估其预期交付所需资源来估算基因组测序经济成本的方法。基因组测序是一种复杂的多步骤分子诊断测试，涉及端到端的工作流程映射，从样本接收、文库处理、测序和数据处理到解释和报告，包括劳动力、生物信息学、设备、耗材和间接成本。尽管已有一些基因组测序的微成本研究，但缺乏详细的成本估算导致了对成本下降的误导性声明和成本的错误描述，并且一直是卫生经济评估中一个众所周知的局限性，这些评估通常将实验室收费而非基因组测序的资源成本估算纳入其中。
Biomarker testing for lysosomal diseases: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
溶酶体疾病生物标志物检测：美国医学遗传学与基因组学学会（ACMG）技术标准
Authors: Stiles, Ashlee R., Donti, Taraka R., Hall, Patricia L., Wilcox, William R.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101242
Abstract
Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb3), glucosylsphingosine (lyso-Gb1), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc4) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.
摘要
溶酶体疾病（LD）生物标志物的测量可以揭示有关疾病状态的宝贵信息。溶酶体球三酰胺神经酰胺（lyso-Gb3）、葡萄糖神经酰胺（lyso-Gb1）、半乳糖神经酰胺（精神苷）和葡萄糖四糖（Glca1-6Glca1-4Glca1-4Glc，Glc4）分别是与法布里病、戈谢病、克拉贝病和庞贝病相关的生物标志物。临床生物标志物检测用于指导患者管理，包括监测疾病进展和启动治疗，以及对有症状患者或无症状但有家族史或新生儿筛查异常的个体进行诊断评估。生物标志物分析可以通过单一分析物的独立分析进行，也可以通过使用液相色谱分离和串联质谱检测的多重分析方法测量多种疾病的分析物。这些指南旨在为生物标志物分析、结果解释和结果报告提供技术标准，以法布里病、戈谢病、克拉贝病和庞贝病为例进行说明。
Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries
基于gnomAD v4.0数据在不同祖先中估算常染色体和X连锁隐性遗传疾病的携带者频率
Authors: Hotakainen, Ronja, Järvinen, Timo, Kettunen, Kaisa, Anttonen, Anna-Kaisa, Jakkula, Eveliina
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101304
Abstract
Purpose:Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF).Methods:We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group.Results:In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%.Conclusion:Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.
摘要
目的：单基因罕见疾病对婴儿死亡和儿科住院贡献显著，并给患者及其家人带来负担。美国医学遗传学与基因组学学会在2021年建议，在计划或怀孕期间，应对携带者频率≥1/200且表型严重或中度的常染色体隐性和X连锁疾病进行携带者筛查。2023年11月发布的gnomAD v4.0包含总共807,162个个体，比之前用于估算基因携带者频率（GCF）的版本大近5倍。方法：我们利用gnomAD v4.0（GRCh38）为可用的遗传祖先群体计算GCF，针对ClinVar中分类为致病性或可能致病性（>80%提交）的变异。我们分别计算了外显子组和基因组的GCF，合并数据，并按遗传祖先群体计算了高风险夫妇频率（ACF）。结果：总共324个基因在至少1个祖先亚群中GCF≥1/200。不同亚群间GCF≥1/200的基因数量差异很大。ACF较为相似，阿什肯纳兹犹太人具有最高的ACF，为6.11%。结论：对携带者风险的深入了解和更新的携带者筛查内容将使患者能够做出更明智的生育决策。
Trends in and Predictors of Patient Pharmacogenomic Test Uptake in a National Healthcare System
国家医疗系统中患者药物基因组学检测采用的趋势及预测因素
Authors: Silva, Abigail, Voora, Deepak, Wu, Rebekah Ryanne, Bartle, Brian, Chanfreau-Coffinier, Catherine, Hung, Allison, Voils, Corrine I.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101308
Abstract
Purpose:Better understanding patient uptake of pharmacogenomic (PGx) testing may inform its implementation and maximize the benefits that such testing can confer. This study examined patient and provider factors associated with PGx test ordering in a national healthcare system where panel-based testing was implemented as part of routine care.Methods:We used a retrospective matched cohort design and data from the Veterans Health Administration Corporate Data Warehouse. A conditional logistic model was used to identify factors associated with a PGx order receipt and estimate odds ratios and 95% confidence intervals.Results:The following patient factors predicted receipt of a PGx test order: younger age, married status, rural residence, non-Hispanic Black or Hispanic race/ethnicity, PGx educational mailer receipt, depression diagnosis, allergy to a drug on the panel, prescriptions for drugs on the panel, and specialty care visits (p<0.05). Additionally, patients whose providers were female, younger, a nurse practitioner/physician assistant or pharmacist, or participated in an educational mailer program were more likely to receive an order (p<0.05).Conclusion:This study highlights factors that may facilitate or hinder the widespread and equitable implementation of PGx testing in a large national healthcare system. The information is being used to further refine the program.
摘要
目的：更好地了解患者对药物基因组学（PGx）检测的采用情况可能有助于其实施，并最大化此类检测可带来的益处。本研究考察了在一个将基于面板的检测作为常规护理的一部分实施的国家医疗系统中，与PGx检测订单相关的患者和医疗提供者因素。方法：我们使用回顾性匹配队列设计和退伍军人健康管理局企业数据仓库的数据。采用条件逻辑模型来识别与PGx订单接收相关的因素，并估算比值比和95%置信区间。结果：以下患者因素预测了PGx检测订单的接收：年龄较轻、已婚状态、农村居住、非西班牙裔黑人或西班牙裔种族/民族、接收PGx教育邮件、抑郁症诊断、对面板上药物过敏、面板上药物处方以及专科就诊（p<0.05）。此外，医疗提供者为女性、年龄较轻、为护理师/医师助理或药剂师，或参与教育邮件计划的患者更有可能接收到订单（p<0.05）。结论：本研究突出了可能促进或阻碍PGx检测在大型国家医疗系统中广泛和公平实施的因素。这些信息正被用于进一步完善该计划。
Primary care provider practices, attitudes, and confidence with hereditary cancer risk assessment and testing: A mixed methods study
初级保健提供者对遗传性癌症风险评估和检测的实践、态度和信心：一项混合方法研究
Authors: Conner, Sarah, Theoryn, Tesla, Dusic, Emerson, Beers, Faith, Knerr, Sarah, Norquist, Barbara, Shirts, Brian H., Bowen, Deborah, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101307
Abstract
Purpose:This study sought to better understand primary care providers' (PCPs) readiness to conduct population-based risk assessment and offer genetic testing for hereditary cancer.Methods:Sixty PCPs completed a survey assessing their current practices, attitudes, and confidence with cancer risk assessment and testing. Sixteen participated in follow-up interviews. Descriptive statistics are presented and supported by qualitative data.Results:Providers preferred direct questioning over standardized screening tools. In interviews, providers said they are not ordering cancer-risk genetic testing even when it might be appropriate. Ninety-eight percent agree testing is important to clinical care, but 73% agree that it could negatively impact patients. Ninety percent were willing to offer targeted testing, but only 68% were willing to offer population-based risk assessment. Confidence performing different behaviors necessary in a cancer risk assessment varied, with only 32% confident responding to questions specifically related to genetic testing.Conclusion:Providers are willing to offer genetic testing, but unlikely to do so because they lack confidence in genetics-specific skill areas. Unsystematic approaches to family history screening and fears about follow up complexity may exacerbate health disparities. Interventions to increase provider confidence in ascertaining and managing hereditary cancer are needed to achieve widespread adoption of population-based risk assessment and guideline-recommended genetic testing.
摘要
目的：本研究旨在更好地了解初级保健提供者（PCPs）对开展基于人群的风险评估和提供遗传性癌症基因检测的准备程度。方法：60名PCPs完成了一项调查，评估他们当前对癌症风险评估和检测的实践、态度和信心。其中16名参与了后续访谈。研究呈现了描述性统计结果，并辅以定性数据。结果：提供者更倾向于直接询问而非使用标准化筛查工具。在访谈中，提供者表示即使在可能适合的情况下，他们也不会订购癌症风险基因检测。98%的人同意检测对临床护理很重要，但73%的人认为它可能对患者产生负面影响。90%的人愿意提供针对性检测，但只有68%的人愿意提供基于人群的风险评估。在癌症风险评估中执行不同行为的信心程度各不相同，只有32%的人对回答特别与基因检测相关的问题有信心。结论：提供者愿意提供基因检测，但由于缺乏遗传学特定技能领域的信心而不太可能这样做。家族史筛查方法的不系统性和对后续复杂性的担忧可能会加剧健康差异。需要采取干预措施来提高提供者在确定和管理遗传性癌症方面的信心，以实现基于人群的风险评估和指南推荐的基因检测的广泛采用。
The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) for Prenatal Care: Initial evidence of content and construct validity
产前护理临床报告的基因检测效用指数（C-GUIDE）：内容和构建效度的初步证据
Authors: Hayeems, Robin Z., Luca, Stephanie, Xiao, Bowen, Boswell-Patterson, Christie, Lavin Venegas, Carolina, Abi Semaan, Clarissa R., Kolar, Tessa, Myles-Reid, Diane, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101306
Abstract
Purpose:To develop and assess the face and construct validity of the Clinician-reported Genetic Testing Utility Index (C-GUIDE) for genetic testing in prenatal care.Methods:After a literature review and consultation with clinical experts, a preliminary draft of C-GUIDE Prenatal was developed. Its face and content validity were then assessed by 19 prenatal genetics' providers using interviews and surveys. Feedback informed further revisions. To test construct validity, 4 geneticist raters completed C-GUIDE on a retrospective sample of cases that received prenatal genetic testing and completed a concurrent global assessment of utility of these cases using an anchor item. A generalized estimating equations model was used to adjust for rater correlation and measure the association between C-GUIDE scores, global item scores, and potential clinical variables.Results:To develop C-GUIDE Prenatal, 7 items were removed, 10 items were modified, and 4 items were added. For 101 cases rated for validation, on average, a 1-point increase in the global item score was associated with an increase of 1.1 in the C-GUIDE score (P = .04). Compared with uninformative results, informative positive and informative negative results were associated with a mean increase of 10.7 (SE = 1.05) (P < .001) and 5.6 (SE = 1.85) (P < .001), respectively. As indications for testing, known/familial variants were associated with a mean increase in the C-GUIDE score of 4.7 (SE = 2.21) (P < .001) compared with ultrasound findings. C-GUIDE scores increased by a mean of 3.0 (SE = 0.23) among cases for whom pregnancies were ongoing compared with those for whom they were not (P < .01).Conclusion:The significant positive associations between C-GUIDE total and the global item score and between C-GUIDE total, result type, indication for testing, and pregnancy status in the expected directions provide evidence of construct validity.
摘要
目的：开发并评估产前护理中基因检测的临床报告基因检测效用指数（C-GUIDE）的表面效度和构建效度。方法：在文献综述和咨询临床专家后，制定了C-GUIDE产前版的初步草案。随后，19名产前遗传学提供者通过访谈和调查评估了其表面效度和内容效度。根据反馈进行了进一步修订。为测试构建效度，4名遗传学家对接受产前基因检测的回顾性样本案例完成了C-GUIDE评分，并使用锚定项目对这些案例的效用进行了同步全局评估。使用广义估计方程模型调整评分者相关性，并测量C-GUIDE得分、全局项目得分和潜在临床变量之间的关联。结果：在开发C-GUIDE产前版过程中，删除了7个项目，修改了10个项目，添加了4个项目。对101个用于验证的案例进行评分，平均而言，全局项目得分每增加1分，C-GUIDE得分增加1.1（P = .04）。与无信息结果相比，有信息阳性和有信息阴性结果分别与C-GUIDE得分平均增加10.7（SE = 1.05）（P < .001）和5.6（SE = 1.85）（P < .001）相关。作为检测指征，已知/家族变异与C-GUIDE得分平均增加4.7（SE = 2.21）（P < .001）相关，相比于超声发现。在妊娠持续的案例中，C-GUIDE得分平均增加3.0（SE = 0.23），相比于妊娠未持续的案例（P < .01）。结论：C-GUIDE总分与全局项目得分之间，以及C-GUIDE总分与结果类型、检测指征和妊娠状态之间在预期方向上的显著正相关，为构建效度提供了证据。
Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)
CanVIG-UK（英国癌症变异解释小组）为遗传学临床医生和临床科学家制定的高外显率癌症易感基因中降低外显率变异的分类框架
Authors: Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101305
Abstract
Purpose:Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.Methods:A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group.Results:CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (A) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (B) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data.Conclusions:CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts.
摘要
目的：目前的做法是将给定癌症易感基因（CSG）中可能致病/致病的变异报告和管理为具有相同外显率，尽管越来越多的证据表明变异之间的风险关联存在差异。使用现有的变异解释方法（主要基于完全外显率模型），可能会对外显率降低的变异进行不一致的分类和/或将其归类为意义不明确的变异（VUS）。我们旨在通过英国癌症变异解释小组（CanVIG-UK）多学科网络为此类变异制定全国性共识方法。方法：在CanVIG-UK月度会议期间和会议之间，就可能表明外显率降低的各种情况进行了一系列调查和现场投票。这些信息为CanVIG-UK指导和咨询小组（CStAG）工作组制定降低外显率变异分类框架提供了迭代发展的依据。结果：CanVIG-UK制定了对2015年ACMG/AMP变异解释框架的修订建议，适用于以下情况：（A）有活跃证据表明外显率效应大小降低（例如来自病例对照或遗传分离数据）；（B）从较弱/可能不一致的观察数据推断出外显率效应降低。结论：CanVIG-UK提出了一个用于分类高外显率基因中降低外显率变异的框架。这些原则虽然是为CSG开发的，但可能适用于其他临床情境。
Impact of early diagnosis, disease variant, and quality of care on the neurocognitive outcome in maple syrup urine disease: a meta-analysis
早期诊断、疾病变异和护理质量对枫糖尿病神经认知结果的影响：一项元分析
Authors: Scharre, Svenja, Mengler, Katharina, Schnabel, Elena, Hübschmann, Oya Kuseyri, Tuncel, Ali Tunç, Hoffmann GF, Georg Friedrich, Garbade, Sven F., Mütze, Ulrike, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101303
Abstract
Purpose:Maple syrup urine disease (MSUD) is a rare inherited metabolic disease characterized by recurrent metabolic decompensations, neurocognitive impairment, and limited life expectancy. This meta-analysis aims to evaluate the impact of early diagnosis by newborn screening (NBS) on mortality and neurocognitive outcome in survivors, taking into account the quality of national health care systems.Methods:Systematic literature search was performed according to Preferred Reporting Items for Systematic Review and Meta-Analysis protocol. Effects on outcome parameters were analyzed using meta-analytical measures and reanalysis of individual participant data.Results:Thirty-three studies were included, reporting on 1141 individuals with MSUD. Participants with classic MSUD presented a more severe phenotype compared with variant MSUD as demonstrated by higher mortality rate (17.1% versus 0%), and lower median IQ (90 versus 104; P < .001, linear mixed model). NBS was associated with improved cognition (mean IQ: 95 versus 82; P = .014, random effects model) and decreased mortality (3% versus 14.6%; P = .028, Kaplan-Meier estimates) compared with individuals identified after onset of symptoms, in trend even after the exclusion of individuals with variant MSUD. Quality of national health care systems correlated with survival (P = .025, meta-regression) and permanent neurological symptoms (P = .031, meta-regression).Conclusion:NBS is a prerequisite to improved outcome in individuals with MSUD; however, health benefit critically depends on the quality of the national health care systems.
摘要
目的：枫糖尿病（MSUD）是一种罕见的遗传性代谢疾病，特征为反复发生代谢失调、神经认知障碍和有限的预期寿命。本元分析旨在评估新生儿筛查（NBS）早期诊断对死亡率和幸存者神经认知结果的影响，同时考虑国家医疗保健系统的质量。方法：按照系统综述和元分析首选报告项目（PRISMA）协议进行系统文献检索。使用元分析方法和个体参与者数据再分析来分析对结果参数的影响。结果：共纳入33项研究，涉及1141名MSUD患者。与变异型MSUD相比，经典型MSUD患者表现出更严重的表型，死亡率更高（17.1%对0%），中位智商更低（90对104；P < .001，线性混合模型）。与症状出现后才被确诊的个体相比，NBS与认知能力改善（平均智商：95对82；P = .014，随机效应模型）和死亡率降低（3%对14.6%；P = .028，Kaplan-Meier估计）相关，即使在排除变异型MSUD个体后，这种趋势仍然存在。国家医疗保健系统的质量与生存率（P = .025，元回归）和永久性神经系统症状（P = .031，元回归）相关。结论：NBS是改善MSUD患者预后的先决条件；然而，健康效益在很大程度上取决于国家医疗保健系统的质量。
The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation
临床基因组资源（ClinGen）：通过全球协作推进基因组知识
Authors: Andersen, Erica F., Azzariti, Danielle R., Babb, Larry, Berg, Jonathan S., Biesecker, Leslie G., Bly, Zo, Buchanan, Adam H., DiStefano, Marina T., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101228
Abstract
The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with >2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on clinicalgenome.org and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen?s knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to https://www.clinicalgenome.org/start.
摘要
临床基因组资源（ClinGen）是一个由美国国立卫生研究院资助的项目，成立于10年前，旨在为医疗和研究用途定义基因和变异的临床相关性。ClinGen工作组制定数据共享和基因组知识整理的标准。专家小组由来自67个国家的2500多名活跃成员组成，他们使用ClinGen标准、基础设施和整理界面，对单基因疾病关系的有效性、遗传变异的致病性、基因剂量敏感性以及基因-疾病干预的可操作性进行整理。结果可在clinicalgenome.org上获取，分类的变异也被提交到由美国国立卫生研究院主办的公开数据库ClinVar。截至2024年1月，已有超过2700个基因被整理（2420个基因-疾病关系的有效性，1557个基因的剂量敏感性，以及447个基因-疾病对的可操作性），5161个独特变异被分类为致病性。目前正在开展体细胞癌症、复杂疾病和药物基因组学方面的新工作，并采用系统方法解决公正、平等、多样性和包容性问题。ClinGen的知识可用于构建循证遗传测试面板、解释拷贝数变异、解决变异分类中的差异、指导向患者披露基因组发现，以及评估新的预测算法。要参与ClinGen活动，请访问https://www.clinicalgenome.org/start。
Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid genomic sequencing
通过超快速基因组测序诊断危重婴幼儿线粒体疾病
Authors: Ball, Megan, Bouffler, Sophie E., Barnett, Christopher B., Freckmann, Mary-Louise, Hunter, Matthew F., Kamien, Benjamin, Kassahn, Karin S., Lunke, Sebastian, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101293
Abstract
Purpose:To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.Methods:Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.Results:A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.Conclusion:Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.
摘要
目的：描述作为国家计划一部分，接受超快速基因组检测的疑似线粒体疾病(MD)危重婴幼儿队列的诊断和临床结果。方法：对454个家庭进行了超快速基因组测序（基因组测序：n=290，外显子组测序+/-线粒体DNA测序：n=164）。在91名个体中，考虑到MD的可能性，使用MD虚拟基因面板进行分析。对这些个体进行了回顾性审查，并根据修改后的奈梅亨线粒体疾病标准进行评分。结果：47%（43/91）的个体获得了诊断，其中40%（17/43）被诊断为MD。另外7名最初未被怀疑患有MD的个体在更广泛的分析后被诊断为MD。基于基因无关的分析导致发现了2个新的致病基因，其致病性通过靶向功能研究得到验证（CRLS1和MRPL39）。功能研究还使另外4名个体获得诊断。在最终被诊断为MD的24名个体中，79%的管理方式发生了改变，其中53%的护理被重新定向为姑息治疗。结论：对急性病重婴幼儿进行超快速MD基因诊断对指导是否需要额外检查和临床管理决策至关重要。
Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic
三级医疗诊所中疑似神经遗传疾病患者遗传诊断相关的临床因素
Authors: Wong, Nicole R., Klomhaus, Alexandra, Adams, David J., Schneider, Benjamin N., Mehta, Sunil, DiStefano, Charlotte, Wilson, Rujuta B., Martinez-Agosto, Julian A., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101252
Abstract
Purpose:This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.Methods:We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.Results:Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.Conclusion:Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.
摘要
目的：本研究旨在识别神经发育障碍患者中与遗传诊断相关的表型因素，并生成一个决策树，以协助临床医生识别最有可能在遗传测试中获得阳性结果的患者。方法：我们回顾性审查了2014年至2019年间在神经发育诊所接受评估的316名患者的病历。根据遗传测试结果对患者进行分类。进行分析以识别区分有无遗传诊断患者的变量。结果：有遗传诊断的患者更可能是女性，并有运动发育迟缓、肌张力低下、先天性心脏病和早期干预的病史。分类和回归树分析显示，75%有运动发育迟缓的患者有遗传诊断。在没有运动发育迟缓的患者中，肌张力低下、开始行走的年龄和首次评估的年龄是遗传诊断的重要指标。结论：我们的发现表明，运动发育迟缓和肌张力低下与神经发育障碍儿童的遗传诊断相关。决策树突出了风险较高的患者亚群，并提出了可能的表型筛查。未来的研究可以基于表型数据开发经验证的决策树，以协助临床医生对遗传测试患者进行分层。
Leveraging Clinical Intuition to Improve Accuracy of Phenotype-Driven Prioritization
利用临床直觉提高表型驱动优先排序的准确性
Authors: Beckwith, Martha A., Danis, Daniel, Bridges, Yasemin, Jacobsen, Julius O.B., Smedley, Damian, Robinson, Peter N.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101292
Abstract
Purpose:Clinical intuition is commonly incorporated into the differential diagnosis as an assessment of the likelihood of candidate diagnoses based either on the patient population being seen in a specific clinic or on the signs and symptoms of the initial presentation. Algorithms to support diagnostic sequencing in individuals with a suspected rare genetic disease do not yet incorporate intuition and instead assume that each Mendelian disease has an equal pretest probability.Methods:The LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) algorithm calculates the likelihood ratio of clinical manifestations represented by Human Phenotype Ontology terms to rank candidate diagnoses. The initial version of LIRICAL assumed an equal pretest probability for each disease in its calculation of the posttest probability (where the test is diagnostic exome or genome sequencing). We introduce Clinical Intuition for Likelihood Ratios (ClintLR), an extension of the LIRICAL algorithm that boosts the pretest probability of groups of related diseases deemed to be more likely.Results:The average rank of the correct diagnosis in simulations using ClintLR showed a statistically significant improvement over a range of adjustment factors.Conclusion:ClintLR successfully encodes clinical intuition to improve ranking of rare diseases in diagnostic sequencing. ClintLR is freely available at https://github.com/TheJacksonLaboratory/ClintLR.
摘要
目的：临床直觉通常被纳入鉴别诊断中，作为对候选诊断可能性的评估，这种评估基于特定诊所接诊的患者群体或初始表现的体征和症状。支持疑似罕见遗传病患者诊断测序的算法尚未纳入直觉，而是假设每种孟德尔疾病具有相等的检验前概率。方法：临床异常似然比解释（LIRICAL）算法计算由人类表型本体术语表示的临床表现的似然比，以对候选诊断进行排序。LIRICAL的初始版本在计算检验后概率时（其中检验指诊断性外显子或基因组测序）假设每种疾病具有相等的检验前概率。我们引入了临床直觉似然比（ClintLR），这是LIRICAL算法的扩展，它提高了被认为更可能的相关疾病组的检验前概率。结果：在模拟中使用ClintLR时，正确诊断的平均排名在一系列调整因子下显示出统计学上的显著改善。结论：ClintLR成功地编码了临床直觉，以改善诊断测序中罕见疾病的排序。ClintLR可在https://github.com/TheJacksonLaboratory/ClintLR免费获取。
Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and Polygenic Risk Scores to inform Colorectal Cancer screening
林奇综合征和多基因风险评分的全人群基因组筛查在结直肠癌筛查中的成本效益分析
Authors: Jiang, Shangqing, Guzauskas, Gregory F., Garbett, Shawn, Graves, John A., Williams, Marc S., Hao, Jing, Zhu, Jinyi, Jarvik, Gail P., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101285
Abstract
Introduction:Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize Colorectal Cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies.Methods:We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening to standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of "no CRC", CRC stages (A-D) and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions.Results:Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared to SOC. The incremental cost-effectiveness ratio (ICER) was $124,415 per quality-adjusted life-year (QALY); screening had a 69% probability of being cost-effective using a willingness to pay threshold of $150,000/QALY. Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared to 95th, 85th, and 80th percentiles.Conclusion:Population-level LS+PRS screening is marginally cost-effective and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.
摘要
引言：基因组筛查可识别林奇综合征（LS）患者和具有高多基因风险评分（PRS）的个体，有望实现结直肠癌（CRC）筛查的个体化。了解其临床和经济影响对制定筛查指南和报销政策至关重要。方法：我们开发了一个马尔可夫模型来模拟个体的终身情况。我们比较了30岁美国成年人群中LS+PRS基因组筛查与标准护理（SOC）的效果。马尔可夫模型包括"无CRC"、CRC各期（A-D）和死亡等健康状态。我们估算了不同干预措施下人群的发病率、死亡率和折现经济结果。结果：对1000人进行LS+PRS筛查与SOC相比，可减少1.36例CRC病例和0.65例死亡。增量成本效益比（ICER）为每质量调整生命年（QALY）124,415美元；使用150,000美元/QALY的支付意愿阈值，筛查有69%的概率具有成本效益。将PRS阈值设定在LS+PRS筛查计划的第90百分位来定义高风险个体，与第95、85和80百分位相比最有可能具有成本效益。结论：人群水平的LS+PRS筛查具有边际成本效益，第90百分位的阈值比其他阈值更可能具有成本效益。
Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy
ARID1A和ARID1B的微重复导致一种新型临床和表观遗传学上独特的BAF病
Authors: van der Sluijs, Pleuntje J., Moutton, Sébastien, Dingemans, Alexander J.M., Weis, Denisa, Levy, Michael A., Boycott, Kym M., Arberas, Claudia, Baldassarri, Margherita, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101283
Abstract
Purpose:ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype.Methods:We collected patients with duplications encompassing ARID1A and ARID1B duplications.Results:16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic.Conclusion:Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.
摘要
目的：ARID1A/ARID1B单倍体不足导致Coffin-Siris综合征，ARID1A的重复导致一种独特的临床综合征，而ARID1B的重复尚未与特定表型相关联。方法：我们收集了包含ARID1A和ARID1B重复的患者。结果：研究包括16例ARID1A重复和13例ARID1B重复病例，ARID1A重复大小范围为0.1至1.2 Mb（1-44个基因），ARID1B重复大小范围为0.9至10.3 Mb（2-101个基因）。两组患者共享一些特征，但ARID1A患者的智力障碍、生长迟缓和先天性异常更为严重。DNA甲基化分析显示，ARID1A患者在血液中有特定的甲基化模式，与对照组和ARID1A或ARID1B功能缺失变异患者不同。ARID1B患者似乎有一种独特的甲基化模式，类似于ARID1A重复患者，但需要进一步研究来验证这些结果。使用PhenoScore和DNA甲基化重新分析评估了5例最初注释为意义不明确重复的ARID1A或ARID1B重复病例，结果将2例ARID1A重复和2例ARID1B重复重新分类为致病性。结论：我们的发现揭示ARID1B重复表现出临床表型，ARID1A重复具有独特的表观遗传特征，与ARID1B重复的特征重叠，为由全基因重复而非单倍体不足引起的一种独特的新兴BAF病提供了进一步的证据。
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder
阐明肌醇多磷酸酶 INPP4A 相关神经发育障碍的临床和遗传谱系
Authors: Rawlins, Lettie E., Maroofian, Reza, Cannon, Stuart J., Daana, Muhannad, Zamani, Mina, Ghani, Shamsul, Leslie, Joseph S., Ubeyratna, Nishanka, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101278
Abstract
Purpose:Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.Methods:Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.Results:We characterize a clinically variable disorder with cardinal features including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/-mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.Conclusion:Our studies comprehensively characterise INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.
摘要
目的：近期的个案报告将双等位基因 INPP4A 变异与严重的神经发育疾病相关联。本研究旨在扩展并阐明其临床-遗传谱系，并为基因型-表型相关性提供病理机制解释。方法：对30名个体进行临床和基因组调查，同时进行分子和计算机模拟以及翻译重新启动研究。结果：我们描述了一种临床表现多样的疾病，其主要特征包括全面发育迟缓、重度至极重度智力障碍、小头畸形、肢体无力、小脑体征和身材矮小。与第4外显子下游的双等位基因 INPP4A 变异相关的更严重表现还包括（桥）小脑发育不全、大脑体积减小、周围痉挛、挛缩、难治性癫痫和皮质视觉障碍。我们的研究确定了这种基因型-表型相关性的可能病理机制，涉及第4外显子的翻译重新启动，产生一种保留部分功能的N端截短 INPP4A 蛋白，与较轻的疾病相关。我们还在 Inpp4a-/- 小鼠模型中发现了相同的重新启动位点保守性，显示类似的基因型-表型相关性。此外，我们发现来自一名受影响个体的成纤维细胞表现出内吞运输通路的破坏，表明了该疾病的潜在生物学基础。结论：我们的研究全面描述了 INPP4A 相关神经发育障碍，并提出了基于基因型的特定临床评估指南。我们提出观察到的基因型-表型相关性的潜在机制基础涉及第4外显子的翻译重新启动。
Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum
胆碱和乙醇胺转运蛋白FLVCR1的双等位基因变异导致严重的发育障碍谱系
Authors: Calame, Daniel G., Wong, Jovi Huixin, Panda, Puravi, Nguyen, Dat Tuan, Leong, Nancy C.P., Sangermano, Riccardo, Patankar, Sohil G., Abdel-Hamid, Mohamed S., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101273
Abstract
Purpose:FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1-/-mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.Methods:We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.Results:We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with Flvcr1-/-mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.Conclusion:These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.
摘要
目的：FLVCR1编码一种溶质载体蛋白，参与血红素、胆碱和乙醇胺的转运。虽然Flvcr1-/-小鼠表现出类似于Diamond-Blackfan贫血（DBA）的骨骼畸形和红细胞生成缺陷，但人类FLVCR1的双等位基因变异此前仅与儿童或成人发病的共济失调、感觉神经病变和视网膜色素变性有关。方法：我们通过国际数据共享识别出患有未确诊神经发育障碍和FLVCR1双等位基因变异的个体，并对其FLVCR1变异的功能后果进行了表征。结果：我们确认了来自23个无关家庭的30名患有FLVCR1双等位基因变异的患者，并描述了一种新的FLVCR1相关表型：严重的发育障碍，伴有严重的发育迟缓、小头畸形（z分数-2.5至-10.5）、脑畸形、癫痫、痉挛和早夭。脑畸形程度从轻度脑容积减少到无脑畸形不等。严重受影响的患者与Flvcr1-/-小鼠和DBA患者共享特征，包括巨细胞性贫血和骨骼畸形。FLVCR1变异显著降低了胆碱和乙醇胺的转运和/或破坏了mRNA剪接。结论：这些数据表明FLVCR1相关表型谱广泛，从类似DBA的严重多器官发育障碍到成人发病的神经退行性疾病。我们的研究扩展了对孟德尔遗传胆碱和乙醇胺疾病的理解，并说明了预期已知疾病基因具有广泛表型谱的重要性，以及将模式生物数据纳入基因组分析以最大化基因检测产出的重要性。
The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses
澳大利亚基因组线粒体旗舰项目：一项全国性的线粒体诊断计划
Authors: Rius, Rocio, Compton, Alison G., Baker, Naomi L., Balasubramaniam, Shanti, Best, Stephanie, Bhattacharya, Kaustuv, Boggs, Kirsten, Boughtwood, Tiffany, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101271
Abstract
Purpose:Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.Methods:A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.Results:Diagnostic yield was 55% (n = 77) with variants in nuclear (n = 37) and mtDNA (n = 18) MD genes, as well as phenocopy genes (n = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.Conclusion:Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.
摘要
目的：患有线粒体疾病（MD）的家庭常常经历漫长的诊断过程和侵入性检查，但许多人仍未获得分子诊断。由临床医生、诊断专家和研究科学家组成的澳大利亚基因组线粒体旗舰项目开展了一项全国性的前瞻性研究，旨在确定使用血液样本进行单例基因组测序的诊断效用。方法：使用修改后的奈梅亨标准（MNC）招募了140名疑似MD的儿童和成人，并随机分配进行外显子组+线粒体DNA（mtDNA）测序或全基因组测序。结果：诊断率为55%（n=77），包括核基因（n=37）和mtDNA（n=18）MD基因的变异，以及表型拷贝基因（n=22）。77%的诊断确定为核基因病因，与发病年龄无关。儿童发病（71%）的诊断率高于成人发病（31%），非欧洲裔（78%）和欧洲裔（67%）儿童的诊断率相当。对于儿童，较高的MNC评分与更高的诊断率和较少的表型拷贝基因诊断相关。此外，3名成年患者在骨骼肌中发现了mtDNA缺失，而这在血液中最初未被发现。结论：对于疑似MD的个体，特别是儿童期发病和MNC评分较高的患者，使用血液进行基因组测序可以简化诊断路径。
Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders
常染色体隐性和显性ACTL6B相关发育性脑部疾病的临床和遗传学描述
Authors: Cali, Elisa, Quirin, Tania, Rocca, Clarissa, Efthymiou, Stephanie, Riva, Antonella, Marafi, Dana, Zaki, Maha S., Suri, Mohnish, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101251
Abstract
Purpose:This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.Methods:We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.Results:Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing.Conclusion:This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.
摘要
目的：本研究旨在全面描述ACTL6B相关疾病的表型谱，这些疾病此前与常染色体隐性和显性神经发育障碍有关。在分子水平上，核仁蛋白ACTL6B在疾病发生中的作用尚不清楚。方法：我们确定了105名受影响个体，包括39例此前报道的病例，并系统分析了所有个体的详细临床和遗传数据。此外，我们在神经元细胞中进行了敲低实验，以研究ACTL6B在核糖体生物合成中的作用。结果：ACTL6B的双等位基因变异与严重至极重度全面发育迟缓/智力障碍（GDD/ID）、婴儿期难治性癫痫、言语缺失、自闭症特征、肌张力障碍和死亡率增加有关。从头单等位基因变异导致中度至重度GDD/ID、言语缺失和自闭症特征，而癫痫和肌张力障碍较少观察到。两组中常见的发现包括面部畸形特征和脑部异常，如胼胝体发育不良、实质体积减少/萎缩。我们揭示了ACTL6B在核仁中对核糖体生物合成，特别是前rRNA加工过程中起着至关重要的作用。结论：本研究全面描述了ACTL6B相关疾病的常染色体隐性和显性形式的临床谱。它提供了两种形式各自表型的比较分析，提出了合理的分子解释，并建议将其纳入不断扩大的"核糖体病"类别中。
A systematic review and pooled analysis of penetrance estimates of copy number variants associated with neurodevelopment
拷贝数变异与神经发育相关性的系统综述和汇总分析
Authors: Goh, Shuxiang, Thiyagarajan, Lavvina, Dudding-Byth, Tracy, Mark, Pinese, Kirk., Edwin P.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101227
Abstract
Purpose:Many copy-number variants (CNVs) are reported to cause a variety of neurodevelopmental disabilities including intellectual disability, developmental delay, autism, and other phenotypes with incomplete penetrance. Therefore, not all individuals with a pathogenic CNV are affected. Penetrance estimates vary between studies. A systematic review was conducted to clarify CNV penetrance for 83 recurrent CNVs.Methods:A systematic review using PRISMA guidelines (PROSPERO #CRD42021253955) was conducted to identify penetrance estimates for CNVs associated with neurodevelopment. Pooled analysis was performed using forest plots. The Ottawa Risk of Bias Assessment facilitated evaluation.Results:Fifteen studies were reviewed in detail with 9 affected cohorts pooled and compared with the gnomAD v4.0 CNV control cohort of 269,885 individuals. Several CNVs previously associated with nonstatistically significant penetrance estimates now exhibit statistically significant differences, contributing to emerging evidence for their pathogenicity (15q24 duplication [A-D breakpoints], 15q24.2q24.5 deletion and duplication [FBXO22], 17q11.2 duplication [NF1], 17q21.31 duplication [KANSL1] and 22q11.2 distal duplication). Additionally, evidence is presented for the benign nature of some CNVs (15q11.2 duplication [NIPA1] and 2q13 proximal duplication [NPHP1]).Conclusion:This is a large-scale systematic review of CNVs associated with neurodevelopment. A synopsis analyzing penetrance and pathogenicity is provided for each of the 83 recurrent CNVs.
摘要
目的：许多拷贝数变异（CNVs）被报道可导致各种神经发育障碍，包括智力障碍、发育迟缓、自闭症和其他表型，但具有不完全外显率。因此，并非所有携带致病性CNV的个体都会受到影响。不同研究中的外显率估计各不相同。本研究对83种反复出现的CNVs进行了系统综述，以阐明其外显率。方法：遵循PRISMA指南（PROSPERO #CRD42021253955）进行系统综述，以确定与神经发育相关的CNVs的外显率估计。使用森林图进行汇总分析。采用渥太华偏倚风险评估工具进行评估。结果：详细审查了15项研究，其中9个受影响队列进行了汇总，并与gnomAD v4.0 CNV对照队列（269,885人）进行了比较。一些先前与统计学上不显著的外显率估计相关的CNVs现在表现出统计学上显著的差异，为其致病性提供了新的证据（15q24重复[A-D断点]、15q24.2q24.5缺失和重复[FBXO22]、17q11.2重复[NF1]、17q21.31重复[KANSL1]和22q11.2远端重复）。此外，还提供了一些CNVs良性本质的证据（15q11.2重复[NIPA1]和2q13近端重复[NPHP1]）。结论：这是一项关于与神经发育相关的CNVs的大规模系统综述。为83种反复出现的CNVs提供了分析外显率和致病性的概要。
X-linked transient antenatal Bartter syndrome related to MAGED2 gene: enriching the phenotypic description and pathophysiologic investigation
X连锁短暂性产前巴特综合征与MAGED2基因相关：丰富表型描述和病理生理学研究
Authors: Buffet, Alexandre, Filser, Mathilde, Bruel, Alexandra, Dard, Rodolphe, Quibel, Thibaud, Dubucs, Charlotte, Kwon, Theresa, Le Tanno, Pauline, et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101217
Abstract
Purpose:Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women.Methods:We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples.Results:Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women.Conclusion:This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.
摘要
目的：与MAGED2基因致病变异相关的短暂性巴特综合征是最近被描述的产前巴特综合征。尽管其性质是短暂的，但在围产期它是最严重的巴特综合征形式。我们的目标是描述14个新病例，并尝试解释女性中的不完全外显率。方法：我们报告了14个新病例，其中包括3名女性，并回顾了迄今为止描述的40个病例。我们通过对胎儿和成人白细胞以及肾脏样本提取的DNA进行焦磷酸测序，检验了MAGED2是否通过其富含CpG的启动子的差异甲基化进行转录调控的假设。结果：对54名有症状患者数据的分析显示，27%的病例症状自发缓解，41%的病例持续存在并发症，32%的病例死亡。76%的患者报告有临床异常，主要是肾脏异常（52%），心血管异常（29%）和畸形特征（13%）。24%的患者报告有发育迟缓。在基因的所有区域都发现了变异。MAGED2富含CpG的启动子的甲基化分析显示与性别相关，但与年龄、组织或症状存在无关，排除了这一机制在女性不完全外显率中的作用。结论：这项工作丰富了这种最近描述的疾病的表型和遗传学描述，加深了我们对MAGED2病理生理学作用和调控的理解。最后，通过描述患者广泛的预后范围，这项工作为向家庭提供的遗传咨询开启了讨论。
Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders
扩展眼部先天性颅神经发育异常疾病的遗传学和表型研究
Authors: Jurgens, Julie A., Barry, Brenda J., Chan, Wai-Man, MacKinnon, Sarah, Whitman, Mary C., Matos Ruiz, Paola M., Pratt, Brandon M., England, Eleina M., et al.
Journal: Genetics in Medicine
DOI: 10.1016/j.gim.2024.101216
Abstract
Purpose:To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).Methods:We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations.Results:Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses.Conclusion:This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.
摘要
目的：确定未解决的眼部先天性颅神经发育异常疾病（oCCDDs）的遗传病因和基因型/表型关联。方法：我们对467名基因未解决的oCCDDs患者（550名受影响个体和1108名总个体）进行表型分析和外显子组或全基因组测序，结合家系分析、人类和动物模型表型以及新发变异分析，以识别破坏蛋白质编码区域的罕见候选单核苷酸变异、插入/缺失和结构变异。对优先考虑的变异进行致病性分类并评估基因型/表型相关性。结果：分析阐明了表型亚组，在43/467名先证者（9.2%）中识别出致病性/可能致病性变异，并在另外70/467名先证者（15.0%）中优先考虑了意义不明确的变异。这些包括已知和新发现的oCCDD相关基因变异，有时包括oCCDDs的综合征相关基因变异（如MYH10、KIF21B、TGFBR2、TUBB6），符合综合征表型组成但此前未与oCCDD相关的基因（如CDK13、TGFB2），以及与oCCDDs或综合征表型无报道关联的基因（如TUBA4A、KIF5C、CTNNA1、KLB、FGF21），以及与oCCDD表型相似导致误诊的相关基因。结论：本研究表明，未解决的oCCDDs是临床和遗传学上异质性的疾病，常与其他孟德尔遗传病重叠，并提名了许多候选基因供未来复制和功能研究。
An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene
骨骼肌α-肌动蛋白(ACTA1)基因已报道变异的最新进展
Authors: Clayton, Joshua S., Johari, Mridul, Taylor, Rhonda L., Dofash, Lein, Allan, Georgina, Monahan, Gavin, Houweling, Peter J., Ravenscroft, Gianina, et al.
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/6496088
Abstract
The ACTA1 gene encodes skeletal muscle alpha-actin, which forms the core of the sarcomeric thin filament in adult skeletal muscle. ACTA1 represents one of six highly conserved actin proteins that have all been associated with human disease. The first 15 pathogenic variants in ACTA1 were reported in 1999, which expanded to 177 in 2009. Here, we update on the now 607 total variants reported in LOVD, HGMD, and ClinVar, which includes 343 reported pathogenic/likely pathogenic (P/LP) variants. We also provide suggested ACTA1-specific modifications to ACMG variant interpretation guidelines based on our analysis of known variants, gnomAD reports, and pathogenicity in other actin isoforms. Using these criteria, we report a total of 447 P/LP ACTA1 variants. From a clinical perspective, the number of reported ACTA1 disease phenotypes has grown from five to 20, albeit with some overlap. The vast majority (74%) of ACTA1 variants cause nemaline myopathy (NEM), but there are increasing numbers that cause cardiomyopathy and novel phenotypes such as distal myopathy. We highlight challenges associated with identifying genotype?phenotype correlations for ACTA1. Finally, we summarize key animal models and review the current state of preclinical treatments for ACTA1 disease. This update provides important resources and recommendations for the study and interpretation of ACTA1 variants.
摘要
ACTA1基因编码骨骼肌α-肌动蛋白，该蛋白构成成年骨骼肌肌节细肌丝的核心。ACTA1是六种高度保守的肌动蛋白之一，它们均与人类疾病有关。1999年首次报道了ACTA1的15个致病变异，到2009年增加到177个。本文更新了目前在LOVD、HGMD和ClinVar中报道的共607个变异，其中包括343个被报道为致病性/可能致病性(P/LP)的变异。我们还根据已知变异、gnomAD报告和其他肌动蛋白亚型的致病性分析，提出了ACTA1特异性的ACMG变异解释指南修改建议。使用这些标准，我们报告了共447个P/LP ACTA1变异。从临床角度来看，报道的ACTA1疾病表型已从5种增加到20种，尽管存在一些重叠。绝大多数(74%)ACTA1变异导致线粒体肌病(NEM)，但越来越多的变异导致心肌病和远端肌病等新型表型。我们强调了识别ACTA1基因型-表型相关性的挑战。最后，我们总结了关键的动物模型，并回顾了ACTA1疾病临床前治疗的当前状况。本更新为ACTA1变异的研究和解释提供了重要的资源和建议。
Biochemical and Genetic Testing of GAA in Over 30.000 Symptomatic Patients Suspected to Be Affected With Pompe Disease
对30,000多名疑似庞贝氏病患者进行GAA的生化和遗传检测
Authors: Balendran-Braun, Sukirthini, Vinatzer, Ursula, Liebmann-Reindl, Sandra, Lux, Manuela, Oliva, Petra, Sansen, Stefaan, Mechtler, Thomas, Kasper, David C., et al.
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/6248437
Abstract
Pompe disease (PD) is a rare autosomal recessive lysosomal disorder caused by loss-of-function of the α-glucosidase (GAA) gene. The deficient GAA enzyme activity may result in potential life-threatening muscle weakness, thus requiring a rapid diagnosis to initiate therapeutic interventions. In this large retrospective study, we analyzed 30.836 PD suspect samples from 57 countries using a two-step approach utilizing dried blood spots (DBSs): biochemical testing of GAA activity followed by complementary genetic sequencing of GAA in biochemically conspicuous cases. Of these 30.836 samples, 2% (n = 639) were excluded; accordingly, this study consisted of 30.193 cases. Biochemical testing of GAA enzyme activity showed normal values in 28.354 (93.90%) and enzyme activity below the cut-off in 1843 (6.10%) cases. These biochemically suspicious cases were genetically analyzed. We identified 723 Pompe cases with 283 different GAA alterations, and 98 variants have been unpublished so far. The most common variant was the splice variant c.-32-13T>G (IVS1). Looking at the IVS1-genotype, the majority was compound heterozygous (n = 169) and identified in late-onset cases (n = 162). Comparison of early- versus late-onset cases to evaluate whether certain genotypes correlate with the age of onset revealed that homozygosity was predominantly found in infantile (85.65%) and compound heterozygosity in late-onset (76.9%) cases. Analysis of homozygous cases revealed 61% nonsense variants in the early stages and 87% missense variants in the late stages. Mapping of disease-associated (homozygous) missense variants to functional GAA protein domains showed that missense variants were found throughout GAA, but we identified enrichment in the catalytic domain. A strict genotype?phenotype correlation cannot be established; nevertheless, a phenotypic implication of some GAA variants could be drawn (e.g., c.896T>C/p.L299P, c.2015G>A/p.R672Q, and c.-32-13T>G). The combined enzyme activity and genetic testing from DBS cards can reliably identify PD and significantly accelerate diagnosis. We identified new genetic variants that contribute to the spectrum of pathogenic variants of the GAA gene.
摘要
庞贝氏病（PD）是一种罕见的常染色体隐性遗传性溶酶体疾病，由α-葡萄糖苷酶（GAA）基因功能丧失引起。GAA酶活性缺乏可能导致潜在危及生命的肌肉无力，因此需要快速诊断以启动治疗干预。在这项大型回顾性研究中，我们使用两步法分析了来自57个国家的30,836份PD疑似样本，利用干血片（DBSs）进行GAA活性的生化检测，随后对生化可疑病例进行GAA的补充遗传测序。在这30,836份样本中，2%（n=639）被排除；因此，本研究包括30,193例。GAA酶活性的生化检测显示28,354例（93.90%）正常，1,843例（6.10%）酶活性低于临界值。这些生化可疑病例进行了基因分析。我们确定了723例庞贝病病例，涉及283种不同的GAA改变，其中98种变异尚未发表。最常见的变异是剪接变异c.-32-13T>G（IVS1）。就IVS1基因型而言，大多数为复合杂合（n=169），并在晚发型病例中发现（n=162）。比较早发型与晚发型病例以评估某些基因型是否与发病年龄相关，结果显示纯合主要见于婴儿型（85.65%），而复合杂合主要见于晚发型（76.9%）病例。纯合病例分析显示，早期阶段61%为无义变异，晚期阶段87%为错义变异。将疾病相关（纯合）错义变异映射到功能性GAA蛋白结构域显示，错义变异遍布GAA，但我们发现在催化域中富集。虽然无法建立严格的基因型-表型相关性，但可以推断某些GAA变异的表型影响（如c.896T>C/p.L299P、c.2015G>A/p.R672Q和c.-32-13T>G）。结合干血片卡的酶活性和基因检测可以可靠地识别PD并显著加快诊断。我们发现了新的遗传变异，这些变异有助于扩展GAA基因的致病变异谱。
Impact of Gene Modifiers on Cystic Fibrosis Phenotypic Profiles: A Systematic Review
基因修饰因子对囊性纤维化表型谱的影响：系统综述
Authors: Ward, Anastasia, Mauleon, Ramil, Ooi, Chee Y., Rosic, Nedeljka
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/6165547
Abstract
Cystic fibrosis (CF) is a complex monogenic disorder with a large variability in disease severity. Growing evidence suggests that the variation observed depends not only on variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but also on modifier genes. Utilizing five databases (including CINAHL, PubMed, Science Direct, Scopus, and Web of Science), a systematic review was conducted to examine the current literature on the known impacts of genomic variations in modifier genes on the CF disease progression, severity, and therapeutic response. A total of 70 full-text articles describing over 80 gene modifiers associated with CF were selected. The modifier genes included genes associated with the CFTR interactome, the inflammatory response, microbial profiles, and other genes affecting the critical physiological pathways of multiple organ systems, such as the respiratory and gastrointestinal systems. Limitations of the existing literature embrace the lack of clinical studies investigating pharmacogenetic impacts and the significance of gene modifiers on the CF clinical picture, including a limited number of replication and validation studies. Further investigations into other potential gene modifiers using genome-wide association studies are needed to critically explore new therapeutic targets and provide a better understanding of the CF disease phenotype under specific drug treatments.
摘要
囊性纤维化（CF）是一种复杂的单基因疾病，其疾病严重程度存在较大差异。越来越多的证据表明，观察到的变异不仅取决于囊性纤维化跨膜传导调节因子（CFTR）基因的变异，还取决于修饰基因。本研究利用五个数据库（包括CINAHL、PubMed、Science Direct、Scopus和Web of Science）进行系统综述，以检查当前文献中关于修饰基因中基因组变异对CF疾病进展、严重程度和治疗反应的已知影响。共选择了70篇全文文章，描述了80多个与CF相关的基因修饰因子。这些修饰基因包括与CFTR相互作用组、炎症反应、微生物谱相关的基因，以及影响多个器官系统（如呼吸系统和胃肠道系统）关键生理通路的其他基因。现有文献的局限性包括缺乏调查药物基因组学影响的临床研究，以及对基因修饰因子在CF临床表现中的重要性的研究，包括有限数量的重复和验证研究。需要通过全基因组关联研究进一步调查其他潜在的基因修饰因子，以探索新的治疗靶点，并更好地理解特定药物治疗下的CF疾病表型。
Exonic Deletions and Deep Intronic Variants of the SLC26A4 Gene Contribute to the Genetic Diagnosis of Unsolved Patients With Enlarged Vestibular Aqueduct
SLC26A4基因的外显子缺失和深内含子变异有助于未解决的前庭导水管扩大患者的基因诊断
Authors: Tian, Yongan, Liu, Mengli, Lu, Yu, Zhao, Xiaoyan, Yan, Zhiqiang, Sun, Yi, Ma, Jingyuan, Tang, Wenxue, et al.
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/8444122
Abstract
Enlarged vestibular aqueduct (EVA) is a frequently occurring inner ear malformation that associates with sensorineural hearing loss (SNHL), with SLC26A4 being the responsible gene. Based on multiplex PCR enrichment and sequencing of the exonic and flanking regions of the SLC26A4 gene, we developed a panel specifically for EVA and found that up to 95% of EVA patients in our Chinese cohorts carried biallelic SLC26A4 pathogenic variants (M2). In this study, we tried to investigate the genetic etiology of 13 previously undiagnosed EVA patients with monoallelic (M1) or none (M0) SLC26A4 variant using a stepwise approach, including copy number variation (CNV) analysis of multiplex PCR enrichment and next-generation sequencing data, single-molecule real-time (SMRT) sequencing of the whole SLC26A4 gene, whole exome sequencing (WES), and whole genome sequencing (WGS). CNV analysis revealed deletions in Exons 1?3, Exons 5?6, and Exons 9?10 of the SLC26A4 gene in seven patients, and SMRT sequencing identified the same heterozygous deep intronic variant (NM_000441.2:c.304+941C>T) in two patients, resulting in a final diagnosis in 9/13 patients. Notably, the variants of Exons 9?10 deletion and c.304+941C>T have not been reported previously. We further showed that the variant c.304+941C>T led to the exonization of partial AluSz6 element (126?bp) where the variant is located through sequencing of the mRNA extracted from the blood of a heterozygous variant carrier. In conclusion, our stepwise approach improved the diagnosis rate of EVA, expanded the mutational spectrum of the SLC26A4 gene, and highlighted the contribution of exonic deletions and deep intronic variants to EVA.
摘要
前庭导水管扩大（EVA）是一种常见的内耳畸形，与感音神经性听力损失（SNHL）相关，SLC26A4是其责任基因。基于SLC26A4基因外显子及其侧翼区域的多重PCR富集和测序，我们开发了一个专门针对EVA的基因检测panel，发现在我们的中国队列中，高达95%的EVA患者携带双等位基因SLC26A4致病变异（M2）。在本研究中，我们尝试使用逐步方法调查13例先前未诊断的EVA患者的遗传病因，这些患者携带单等位基因（M1）或无（M0）SLC26A4变异。方法包括多重PCR富集和下一代测序数据的拷贝数变异（CNV）分析、SLC26A4全基因的单分子实时（SMRT）测序、全外显子测序（WES）和全基因组测序（WGS）。CNV分析在七名患者中发现了SLC26A4基因的外显子1-3、外显子5-6和外显子9-10的缺失，SMRT测序在两名患者中识别出相同的杂合深内含子变异（NM_000441.2:c.304+941C>T），最终在13名患者中有9名得到诊断。值得注意的是，外显子9-10缺失和c.304+941C>T变异此前未有报道。我们进一步通过测序从一名杂合变异携带者血液中提取的mRNA，显示c.304+941C>T变异导致了变异所在的部分AluSz6元件（126bp）的外显子化。总之，我们的逐步方法提高了EVA的诊断率，扩展了SLC26A4基因的突变谱，并强调了外显子缺失和深内含子变异对EVA的贡献。
Clinical, Pathologic, and Genetic Spectrum of Collagen VI–Related Disorder in China—A Retrospective Observational Multicenter Study
中国胶原蛋白VI相关疾病的临床、病理和遗传谱系——一项回顾性观察多中心研究
Authors: Hu, Chaoping, Shi, Yiyun, Zhao, Lei, Zhu, Wenhua, Jiao, Kexin, Yu, Lifei, Li, Xihua, Wang, Yi
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/3503253
Abstract
Background: Collagen VI-related disorder (COLVI-RD) is one of the most common congenital muscular dystrophies. However, data is limited in China. Methods: We conducted a retrospective study at two tertiary centers. Clinical presentations, lab findings (including serum creatine kinase levels), muscle biopsy, and molecular test results for patients diagnosed with definite COLVI-RD were collected. Results: A total of 82 patients were enrolled in the study, including 4 with early?severe Ullrich congenital muscular dystrophy (E?S UCMD) (4.8%), 45 with moderate?progressive Ullrich congenital muscular dystrophy (M?P UCMD, 54.9%), 19 with mild UCMD (23.2%), and 14 with Bethlem myopathy (BM, 17.1%). Feeding difficulty, DDH, and neurogenic damage were more common in E?S and M?P UCMD, while contracture of distal joints, atrophic scars, and hyperkeratosis was more prominent in mild UCMD and BM. Seventy patients harbored 64 pathogenic mutations in COLVI-related genes: 28 patients in COL6A1 gene, 25 patients in the COL6A2 gene, and 17 patients in the COL6A3 gene, among which 33 mutations were novel. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, which were mostly located in N-terminus of THD, in a dominant pattern, while mutations in the COL6A2 gene were much more polymorphic, which spread throughout the whole length of the gene, in a dominant or recessive pattern. Immunofluorescence dual labeling of Collagen VI/IV in 44 patients showed complete deficiency of Collagen VI in 10 patients (22.7%), sarcolemma-specific Collagen VI deficiency in 25 patients (56.8%), and normal Collagen VI staining in 9 patients (20.5%). Conclusion: Our study reported the largest cohort of COLVI-RD in China, which showed M?P UCMD was the most common phenotype, followed by mild UCMD and BM. We identified 30 novel mutations and expanded the genetic spectrum. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, while mutations in the COL6A2 gene were much more polymorphic. For severe phenotypes, most mutations are sporadic, while some are AD or recessive inherited. For milder phenotypes, sporadic and AD inherited were both common, while only 1 patient with recessive mutations was observed.
摘要
背景：胶原蛋白VI相关疾病（COLVI-RD）是最常见的先天性肌营养不良症之一。然而，中国的相关数据有限。方法：我们在两家三级医疗中心进行了回顾性研究。收集了确诊为COLVI-RD患者的临床表现、实验室检查结果（包括血清肌酸激酶水平）、肌肉活检和分子检测结果。结果：共有82名患者纳入研究，其中4名为早期重度尤利希先天性肌营养不良症（E-S UCMD）（4.8%），45名为中度进行性尤利希先天性肌营养不良症（M-P UCMD，54.9%），19名为轻度UCMD（23.2%），14名为贝特莱姆肌病（BM，17.1%）。进食困难、发育性髋关节脱位和神经源性损伤在E-S和M-P UCMD中更为常见，而远端关节挛缩、萎缩性疤痕和角化过度在轻度UCMD和BM中更为突出。70名患者携带64个COLVI相关基因的致病突变：28名患者在COL6A1基因，25名患者在COL6A2基因，17名患者在COL6A3基因，其中33个突变为新发现。COL6A1和COL6A3基因以错义突变和剪接突变为主，主要位于THD的N端，呈显性模式，而COL6A2基因的突变更加多态性，分布在整个基因长度，呈显性或隐性模式。44名患者的胶原蛋白VI/IV免疫荧光双标记显示，10名患者（22.7%）完全缺乏胶原蛋白VI，25名患者（56.8%）特异性肌膜胶原蛋白VI缺乏，9名患者（20.5%）胶原蛋白VI染色正常。结论：我们的研究报告了中国最大的COLVI-RD队列，显示M-P UCMD是最常见的表型，其次是轻度UCMD和BM。我们发现了30个新的突变，扩展了遗传谱系。COL6A1和COL6A3基因以错义突变和剪接突变为主，而COL6A2基因的突变更加多态性。对于严重表型，大多数突变是散发的，而一些是显性遗传或隐性遗传。对于较轻表型，散发和显性遗传都很常见，而只观察到1例患者有隐性突变。
Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG
基因型/表型关系：来自137名PMM2-CDG患者的经验教训
Authors: Pajusalu, Sander, Vals, Mari-Anne, Serrano, Mercedes, Witters, Peter, Cechova, Anna, Honzik, Tomáš, Edmondson, Andrew C., Ficicioglu, Can, et al.
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/8813121
Abstract
We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs?100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration:NCT03173300.
摘要
我们报告了一项正在进行的国际多中心自然病史研究中最大的单一PMM2-CDG患者数据集。该研究收集了遗传、临床和生物学信息，以评估与先前研究的相似性，报告新发现，并进一步检查潜在的基因型/表型相关性。共有137名参与者具有完整的基因型信息，代表60种独特的变异，其中最常见的是p.Arg141His，占58.4%（n=80）的参与者，其次是p.Pro113Leu（21.2%，n=29）和p.Phe119Leu（12.4%，n=17），这与先前的研究一致。有趣的是，报告了六种新的变异，包括五种错义变异（p.Pro20Leu、p.Tyr64Ser、p.Phe68Cys、p.Tyr76His和p.Arg238His）和一种移码变异（c.696del p.Ala233Argfs?100）。患者表型通过Nijmegen进展CDG评分量表（NPCRS）进行表征，同时结合生化参数，其中最持续失调的是凝血因子，特别是抗凝血酶（79.5%，117例中的93例低于正常值），此外还有因子XI和蛋白C活性。患者基因型根据疾病相关突变的预测致病机制进行分类，其中大多数位于PMM2酶的催化/激活、折叠或二聚化区域。使用了两种不同的方法来揭示基因型/表型关系。第一种方法仅根据预测的致病机制来表征基因型，发现了与生化参数相关的变化，这些变化仅使用NPCRS时并不明显，涉及催化/激活、二聚化、折叠和无蛋白变异。第二种方法通过预测的致病机制和/或当与一组严重的非功能性变异配对时的个别变异来表征基因型，揭示了与NPCRS和生化参数的相关性，表明p.Cys241Ser与较轻的疾病相关，而p.Val231Met、二聚化和折叠变异与更严重的疾病相关。尽管此前为PMM2-CDG确定全面的基因型/表型关系一直具有挑战性，但当前研究中更大的样本量以及生化参数的纳入为遗传学与疾病之间的相互作用提供了新的见解。临床试验注册号：NCT03173300。
Phenotype Correlations With Pathogenic DNA Variants in the MUTYH Gene: A Review of Over 2000 Cases
MUTYH基因致病DNA变异与表型相关性：超过2000例病例的综述
Authors: Thet, Monica, Plazzer, John-Paul, Capella, Gabriel, Latchford, Andrew, Nadeau, Emily A. W., Greenblatt, Marc S., Macrae, Finlay
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/8520275
Abstract
MUTYH-associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic MUTYH variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. This narrative review is aimed at exploring the phenotypic spectrum of MAP to better characterize the MAP phenotype. Literature search was conducted to identify articles reporting on MAP-specific phenotypes. Clinical data from 2109 MAP patients identified from the literature showed that 1123 patients (53.2%) had CRC. Some patients with CRC had no associated adenomas, suggesting that adenomas are not an obligatory component of MAP. Carriers of the two missense founder variants, and possibly truncating variants, had an increased cancer risk when compared to those who carry other pathogenic variants. It has been suggested that somatic G:C?>?T:A transversions are a mutational signature of MAP and could be used as a biomarker in screening and identifying patients with atypical MAP, or in associating certain phenotypes with MAP. The extracolonic and extraintestinal manifestations that have been associated with MAP include duodenal adenomas, duodenal cancer, fundic gland polyps, gastric cancer, ovarian cancer, bladder cancer, and skin cancer. The association of breast cancer and endometrial cancer with MAP remains disputed. Desmoid tumors and congenital hypertrophy of the retinal pigment epithelium (CHRPEs) are rarely reported in MAP but have long been seen in FAP patients and thus could act as a distinguishing feature between the two. This collection of MAP phenotypes will assist in the assessment of pathogenic MUTYH variants using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) Variant Interpretation Guidelines and ultimately improve patient care.
摘要
MUTYH相关性息肉病（MAP）是一种常染色体隐性遗传病，其中宪法性双等位基因MUTYH致病变异的遗传使人易发生腺瘤和结直肠癌（CRC）。它还与结肠外和肠道外表现相关，这些表现可能与家族性腺瘤性息肉病（FAP）的表型重叠。目前，文献中对某些表型是否真正与MAP相关存在分歧。这篇叙述性综述旨在探讨MAP的表型谱，以更好地描述MAP表型。通过文献检索确定报告MAP特定表型的文章。从文献中确定的2109名MAP患者的临床数据显示，1123名患者（53.2%）患有CRC。一些CRC患者没有相关的腺瘤，这表明腺瘤不是MAP的必要组成部分。携带两个错义创始人变异，可能还有截断变异的携带者，与携带其他致病变异的人相比，癌症风险增加。有人提出，体细胞G:C→T:A颠换是MAP的突变特征，可用作筛查和识别非典型MAP患者的生物标志物，或将某些表型与MAP相关联。与MAP相关的结肠外和肠道外表现包括十二指肠腺瘤、十二指肠癌、胃底腺息肉、胃癌、卵巢癌、膀胱癌和皮肤癌。乳腺癌和子宫内膜癌与MAP的关联仍有争议。在MAP中很少报告纤维瘤病和先天性视网膜色素上皮肥大（CHRPEs），但长期以来在FAP患者中观察到，因此可以作为区分两者的特征。这些MAP表型的汇集将有助于使用美国医学遗传学院和分子病理学协会（ACMG/AMP）变异解释指南评估致病MUTYH变异，并最终改善患者护理。
Long-Read Sequencing Identified a PKD1 Gene Conversion in ADPKD Rather Than the False-Positive Exon Deletion Indicated by WES and MLPA
长读序列测序发现ADPKD中的PKD1基因转换，而非WES和MLPA所示的假阳性外显子缺失
Authors: Qiu, Xueping, Jin, Xin, Li, Jin, Zhang, Yuanzhen, Ma, Jianhong, Zheng, Fang
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/7225526
Abstract
Whole exome sequencing (WES) has become an increasingly common technique for identifying the genetic cause of Mendelian genetic diseases. However, it may fail to detect the complex regions of the genome. Here, we investigated the genetic etiology of a pedigree with autosomal dominant polycystic kidney disease (ADPKD) using a combination of WES, multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, and long-read sequencing (LRS). Initially, WES of the proband revealed a heterozygous variant c.7391G>C in PKD1 Exon 18, along with a heterozygous deletion of the 17th and 18th exons of PKD1 detected by exome-based copy number variation (CNV) analysis. MLPA confirmed the PKD1 heterozygous deletion of Exon 18. Except for c.7391G>C, Sanger sequencing identified four other heterozygous variants (c.7278T>C, c.7288C>T, c.7344C>G, and c.7365C>T) in Exon 18 of PKD1. Subsequently, LRS uncovered seven clustered substitution variants (c.7209+28C>T, c.7210-16C>T, c.7278T>C, c.7288C>T, c.7344C>G, c.7365C>T, and c.7391G>C), with six of them omitted by WES due to interference from PKD1 pseudogenes. Combining LRS results with cosegregation of the pedigree analysis, we found these variants were in cis and converted from PKD1 pseudogenes, covering a region of at least 282?bp. Notably, the paralogous sequence variants of c.7288C>T introduced a premature stop codon of PKD1, leading to a function loss, and were classified as pathogenic (PVS1+PS4+PM2) according to the ACMG/AMP guideline. Our study highlights the limitations of WES/MLPA and the importance of utilizing complementary tools like LRS for comprehensive variant detection in PKD1.
摘要
全外显子组测序（WES）已成为鉴定孟德尔遗传病遗传原因的一种越来越常见的技术。然而，它可能无法检测基因组的复杂区域。在此，我们使用WES、多重连接依赖性探针扩增（MLPA）、Sanger测序和长读序列（LRS）测序的组合方法，研究了一个常染色体显性多囊肾病（ADPKD）家系的遗传病因。最初，先证者的WES显示PKD1基因第18外显子存在杂合变异c.7391G>C，同时基于外显子的拷贝数变异（CNV）分析检测到PKD1基因第17和18外显子的杂合缺失。MLPA证实了PKD1基因第18外显子的杂合缺失。除c.7391G>C外，Sanger测序在PKD1基因第18外显子中还发现了四个其他杂合变异（c.7278T>C、c.7288C>T、c.7344C>G和c.7365C>T）。随后，LRS发现了七个聚集的替换变异（c.7209+28C>T、c.7210-16C>T、c.7278T>C、c.7288C>T、c.7344C>G、c.7365C>T和c.7391G>C），其中六个由于PKD1假基因的干扰而被WES遗漏。结合LRS结果和家系共分离分析，我们发现这些变异是顺式的，并从PKD1假基因转换而来，覆盖至少282bp的区域。值得注意的是，c.7288C>T的同源序列变异引入了PKD1的提前终止密码子，导致功能丧失，根据ACMG/AMP指南被归类为致病性（PVS1+PS4+PM2）。我们的研究突出了WES/MLPA的局限性，以及利用LRS等互补工具对PKD1进行全面变异检测的重要性。
Constitutional BRCA1 Epimutations: A Key for Understanding Basal-Like Breast and High-Grade Serous Ovarian Cancer
BRCA1基因的先天性表观突变：理解基底样乳腺癌和高级别浆液性卵巢癌的关键
Authors: Lønning, Per E., Nikolaienko, Oleksii, Knappskog, Stian
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/7353984
Abstract
Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple-negative breast (TNBC) and high-grade serous ovarian cancers (HGSOC). While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently. Conducting a prospective nested case-control study on women participating in the American Women?s Health Initiative Study, we provided firm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies ?5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants. We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers. Future work in the field must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types.
摘要
BRCA1和BRCA2基因的胚系致病性遗传变异是家族性乳腺癌和卵巢癌最常见的原因。与BRCA2相比，BRCA1基因的表观突变在三阴性乳腺癌（TNBC）和高级别浆液性卵巢癌（HGSOC）的组织中经常被检测到。尽管过去十年的研究报告了乳腺癌和卵巢癌患者白血细胞（WBC）中的BRCA1表观突变，但直到最近才正式评估了TNBC和HGSOC发病的潜在危险比。我们对参与美国妇女健康倡议研究的女性进行了前瞻性嵌套病例对照研究，提供了确凿证据表明，即使在等位基因频率<0.1%的情况下，白血细胞中的嵌合型BRCA1表观突变与白血细胞采集5年后HGSOC和TNBC发病风险显著增加相关。在第二项评估TNBC患者白血细胞和匹配肿瘤样本中BRCA1表观突变的研究中，我们的结果表明这种表观突变是约20%TNBC的潜在原因，远超过携带BRCA1胚系致病性遗传变异的病例比例。我们在源自三个胚层的组织中检测到原发性先天BRCA1表观突变。它们独立于BRCA1启动子单倍型，但在受影响个体的所有白血细胞中存在于同一等位基因上。此外，在正常和肿瘤乳腺组织以及白血细胞中，表观突变一致地存在于同一等位基因上。这一发现，加上在新生儿白血细胞中检测到的BRCA1表观突变，强烈表明这是一个影响所有胚层的早期胚胎事件，并伴随克隆扩增。该领域未来的工作必须导致准确理解BRCA1表观突变发生的时间和方式，最重要的是，除BRCA1之外的其他基因的原发性先天表观突变是否可能导致其他癌症类型的风险增加。
Clinical and Genetic Characteristics of Two Cases With Developmental and Epileptic Encephalopathy 93 Caused by Novel ATP6V1A Mutations and Literature Review
ATP6V1A基因新突变导致的发育和癫痫性脑病93型两例病例的临床和遗传特征及文献综述
Authors: Ma, Jian, Zhang, Hongwei, Lv, Yuqiang, Gao, Min, Gai, Zhongtao, Liu, Yi
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/4678670
Abstract
Developmental and epileptic encephalopathy 93 (DEE93) is a new defined autosomal dominant neurologic disorder caused by heterozygous mutations in the ATP6V1A gene on chromosome 3q13. DEE93 is characterized by developmental delay, early-onset refractory seizures, hypotonia, and intellectual disability. So far, merely 31 cases caused by ATP6V1A gene mutation have been reported in literature worldwide, and early genetic detection is required for differential diagnosis. Here, we analyze the clinical and genetic features of two patients with two novel ATP6V1A mutations (c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu)) and expound the therapeutic schedule for epilepsy. We also review the reported mutations and genotypes associated with the disorder. Our study expands the clinical and genetic spectrum of ATP6V1A mutation-associated DEE93, which provides a basis for the diagnosis, treatment, and genetic counseling of the disorder.
摘要
发育和癫痫性脑病93型（DEE93）是一种新定义的常染色体显性遗传神经系统疾病，由3q13染色体上ATP6V1A基因的杂合突变引起。DEE93的特征包括发育迟缓、早发难治性癫痫发作、肌张力低下和智力障碍。迄今为止，全球文献中仅报道了31例由ATP6V1A基因突变引起的病例，需要进行早期基因检测以进行鉴别诊断。在本研究中，我们分析了两名患者的临床和遗传特征，他们携带两种新的ATP6V1A突变（c.1061G>T/p.(Trp354Leu)和c.746C>T/p.(Pro249Leu)），并阐述了癫痫的治疗方案。我们还回顾了与该疾病相关的已报道突变和基因型。我们的研究扩展了ATP6V1A突变相关DEE93的临床和遗传谱系，为该疾病的诊断、治疗和遗传咨询提供了基础。
Estimating the Prevalence of GNE Myopathy Using Population Genetic Databases
利用人群遗传数据库估算GNE肌病的患病率
Authors: Derksen, Alexa, Thompson, Rachel, Shaikh, Madeeha, Spendiff, Sally, Perkins, Theodore J., Lochmüller, Hanns
Journal: Human Mutation
DOI: https://doi.org/10.1155/2024/7377504
Abstract
GNE myopathy (GNEM) is a rare autosomal recessive disorder characterized by progressive skeletal muscle wasting starting in early adulthood. The prevalence of GNEM is estimated to range between one and nine cases per million individuals, but the accuracy of these estimates is limited by underdiagnosis, misdiagnosis, and bias introduced by founder allele frequencies. As GNEM is a recessive disorder, unaffected carriers of single damaging variants can be expected to be found in the healthy population, providing an alternative method for estimating prevalence. We aim to estimate the prevalence of GNEM using allele frequencies obtained from healthy population genetic databases. We performed a review to establish a complete list of all known pathogenic GNEM variants from both literature and variant databases. We then developed standardized filtering steps using in silico tools to predict the pathogenicity of unreported GNE variants of uncertain clinical significance and validated our pathogenicity inferences using Mendelian Approach to Variant Effect pRedICtion built in Keras (MAVERICK) and AlphaMissense. We calculated conservative and liberal disease prevalence estimates using allele frequencies from the Genome Aggregation Database (gnomAD) population database by employing methodologies based on the assumptions of the Hardy?Weinberg Equilibrium. We additionally calculated estimates for disease prevalence removing the contribution of unique variant combinations that either do not cause myopathy in humans or result in embryonic lethality. We present the most comprehensive list of reported pathogenic GNE variants to date, together with additional variants predicted as pathogenic by in silico methods. We provide additional pathogenicity scores for these variants using new pathogenicity prediction tools and present a set of estimates for GNEM prevalence based on the different assumptions. Our most conservative estimate suggested a prevalence of 18.46 cases per million, while our most liberal estimate places the prevalence at 95.42 cases per million. When accounting for variant severity, this range drops to 11.00?87.68 cases per million. Our findings indicate that the true global prevalence of GNEM is greater than previous predictions underscoring that this condition is considerably more widespread than previously believed.
摘要
GNE肌病（GNEM）是一种罕见的常染色体隐性遗传病，特征是从成年早期开始出现进行性骨骼肌萎缩。GNEM的患病率估计在每百万人中有1到9例，但这些估计的准确性受到漏诊、误诊以及创始人等位基因频率引入的偏差的限制。由于GNEM是一种隐性遗传病，预计在健康人群中可以发现单个致病变异的无症状携带者，这为估算患病率提供了另一种方法。我们旨在使用从健康人群遗传数据库获得的等位基因频率来估算GNEM的患病率。我们进行了文献综述，以建立一个完整的已知GNEM致病变异列表，包括文献和变异数据库中的信息。然后，我们使用生物信息学工具开发了标准化的筛选步骤，以预测未报道的GNE变异的临床意义不确定的致病性，并使用基于Keras构建的孟德尔变异效应预测方法（MAVERICK）和AlphaMissense验证了我们的致病性推断。我们使用Genome Aggregation Database（gnomAD）人群数据库中的等位基因频率，基于哈迪-温伯格平衡假设的方法，计算了保守和宽松的疾病患病率估计。我们还计算了去除在人类中不引起肌病或导致胚胎致死的独特变异组合贡献后的疾病患病率估计。我们提供了迄今为止最全面的已报道的GNE致病变异列表，以及通过生物信息学方法预测为致病性的额外变异。我们使用新的致病性预测工具为这些变异提供了额外的致病性评分，并基于不同假设提出了一系列GNEM患病率估计。我们最保守的估计表明患病率为每百万人18.46例，而最宽松的估计将患病率置于每百万人95.42例。考虑变异严重程度后，这个范围降至每百万人11.00-87.68例。我们的发现表明，GNEM的真实全球患病率高于先前的预测，强调这种疾病比先前认为的更为普遍。
Commentary on <em>Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank</em>
对《在英国生物银行中估计Lynch综合征变异携带者的癌症风险》一文的评论
Authors: Vendrell, Xavier, Abulí, Anna, Serra, Clara, Guillén, Juan José, Rueda, Joaquín, García-Planells, Javier, Santos-Simarro, Fernando, Quiroga, Ramiro, et al.
Journal: Journal of Medical Genetics
DOI: 10.1136/jmg-2024-110385
Abstract
In their recent article, Fummey et al1 reported incidences of colorectal cancer (CRC) and other cancers in carriers of pathogenic mismatch repair (path_MMR) variants in a UK Biobank. Although cancer risks with smaller CIs have been determined previously in larger numbers of carriers using the Prospective Lynch Syndrome Database (PLSD),2 the findings from the UK Biobank are important as PLSD is likely to be subject to ascertainment biases given that participants are recruited on the basis of diagnostic or predictive genetic test results. By contrast, carriers in the UK Biobank were identified incidentally during …
摘要
在最近的一篇文章中，Fummey等人报告了英国生物银行中错配修复（path_MMR）致病变异携带者的结直肠癌（CRC）和其他癌症的发病率。尽管之前使用前瞻性Lynch综合征数据库（PLSD）在更大数量的携带者中已经确定了具有较小置信区间的癌症风险，但英国生物银行的研究结果仍然很重要，因为PLSD可能存在选择偏差，其参与者是基于诊断或预测性基因检测结果而招募的。相比之下，英国生物银行中的携带者是在...过程中偶然识别的。
