本文介绍了Phenomics期刊2023年第二期收录的8篇文章合集，文章概览如下，请查收！

（Phenomics期刊2023年第二期封面图）

01 High-Resolution and Multidimensional Phenotypes Can Complement Genomics Data to Diagnose Diseases in the Neonatal Population

多维度表型来源、平台搭建、数据整合以及数据应用示意图

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DOI：

https://doi.org/10.1007/s43657-022-00071-0

引用格式：

Xiao, T., Dong, X., Lu, Y. et al. High-Resolution and Multidimensional Phenotypes Can Complement Genomics Data to Diagnose Diseases in the Neonatal Population. Phenomics 3, 204–215 (2023). https://doi.org/10.1007/s43657-022-00071-0

基因组医学的进步加速了人们对人类疾病的洞察。许多基因组计划对生物医学研究和临床实践产生重大影响，如千人基因组计划、ENCODE、gnomAD、ExAC、BRAIN Initiative以及英国100,000、PFMG2025、中国新生儿基因组项目(CNGP)和美国国立儿童健康与人类发育研究所(NICHD)的新生儿测序(NSIGHT)等。在上述基因组计划中，对新生儿人群的研究一直是重点，这是因为大多数遗传疾病都是婴幼儿发病，且因遗传疾病而死亡的患儿占5岁以下死亡率的10%。此外，有证据表明，在生命早期的诊断可给患儿及其家人带来诸多益处。在基因组医学迅速发展的今天，表型组学的发展相对缓慢，这也意味着对及时诊断的发展将带来阻碍。一方面，利用传统医学方式能获得的新生儿疾病表型相对少，且刻画深度不够，导致目前新生儿表型与基因型之间缺乏有效的对应关系；另一方面，高分辨率和多维表型的缺乏亦限制了新生儿疾病机制的探索进程。因此，在实现新生儿精准诊疗的道路上，完善表型组的构建，建立整合表型组和基因组数据融合的平台是关键。

Abstract

Advances in genomic medicine have greatly improved our understanding of human diseases. However, phenome is not well understood. High-resolution and multidimensional phenotypes have shed light on the mechanisms underlying neonatal diseases in greater details and have the potential to optimize clinical strategies. In this review, we first highlight the value of analyzing traditional phenotypes using a data science approach in the neonatal population. We then discuss recent research on high-resolution, multidimensional, and structured phenotypes in neonatal critical diseases. Finally, we briefly introduce current technologies available for the analysis of multidimensional data and the value that can be provided by integrating these data into clinical practice. In summary, a time series of multidimensional phenome can improve our understanding of disease mechanisms and diagnostic decision-making, stratify patients, and provide clinicians with optimized strategies for therapeutic intervention; however, the available technologies for collecting multidimensional data and the best platform for connecting multiple modalities should be considered.

02 Management of Intraductal Papilloma of the Breast Diagnosed on Core Needle Biopsy: Latest Controversies

IDP概况

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DOI：

https://doi.org/10.1007/s43657-022-00085-8

引用格式：

Tu, S., Yin, Y., Yuan, C. et al. Management of Intraductal Papilloma of the Breast Diagnosed on Core Needle Biopsy: Latest Controversies. Phenomics 3, 190–203 (2023). https://doi.org/10.1007/s43657-022-00085-8

IDP起源于乳管上皮的良性增长，其临床可表现为乳头溢液和乳房肿块。诊断IDP常用的影像学技术有钼靶、数字乳腺断层扫描、超声、磁共振、乳管镜等。组织病理学仍是诊断IDP的金标准。随着影像学及微创技术的发展，除传统手术外，还有多种治疗IDP的手术方式如真空辅助旋切术、乳管镜定位下切除术、钼靶定位下切除术、麦默通微创旋切术。随着医学影像技术和微创手术的进步，IDP的诊断和治疗也在不断更新。然而，目前IDP的病因和发病机制尚不明确且诊断标准不统一，导致其治疗无法规范。IDP面临着诊断不足、治疗不当和复发的可能性。该文总结了临床发现的IDP的高危因素，希望有助于更精准更有效的治疗。目前，经活检诊断为无异型性且无症状的IDP患者，其治疗正由手术切除转向影像学随访。另一方面，对于存在高危因素的IDP病例，应谨慎选择保守治疗。

Abstract

Intraductal papillomas (IDPs), including central papilloma and peripheral papilloma, are common in the female population. Due to the lack of specific clinical manifestations of IDPs, it is easy to misdiagnose or miss diagnose. The difficulty of differential diagnosis using imaging techniques also contributes to these conditions. Histopathology is the gold standard for the diagnosis of IDPs while the possibility of under sample exists in the percutaneous biopsy. There have been some debates about how to treat asymptomatic IDPs without atypia diagnosed on core needle biopsy (CNB), especially when the upgrade rate to carcinoma is considered. This article concludes that further surgery is recommended for IDPs without atypia diagnosed on CNB who have high-risk factors, while appropriate imaging follow-up may be suitable for those without risk factors.

03 Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing

工作流程

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DOI：

https://doi.org/10.1007/s43657-022-00062-1

引用格式：

Fu, F., Tao, X., Jiang, Z. et al. Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing. Phenomics 3, 182–189 (2023). https://doi.org/10.1007/s43657-022-00062-1

越来越多从不吸烟的年轻人被诊断出患有肺癌。该研究的目的是研究这些患者的肺癌遗传易感性，并发现年轻不吸烟者肺腺癌的候选致病变异，收集了123名40岁以前诊断为肺腺癌的从不吸烟的东亚患者的外周血。对提取的外周血细胞基因组DNA进行全外显子组测序(WES)并鉴定出3481个单核苷酸变异。通过生物信息学工具和结合已发表的与癌症遗传易感性相关的基因列表，在10个种系基因中检测到致病变异:ATR、FANCD2、FANCE、GATA2、HFE、MSH2、PDGFRA、PMS2、SDHB和WAS。致病变异的患者多发生在女性(9/ 10,90.0%)和IV期肺腺癌(4/ 10,40%)。此外，17个基因(ASB18、B3GALT5、CLEC4F、COL6A6、CYP4B1、C6orf132、EXO1、GATA4、HCK、KCP、NPHP4、PIGX、PPIL2、PPP1R3G、RRBP1、SALL4和TTC28)的种系突变在至少两名患者中发生，显示出潜在的致病作用。基因本体论分析进一步表明，这些种系突变基因主要位于核质中，与DNA修复相关的生物学过程有关。

Abstract

Recently, an increasing number of young never-smokers are diagnosed with lung cancer. The aim of this study is to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers. Peripheral blood was collected from 123 never-smoking east-Asian patients diagnosed with lung adenocarcinoma before the age of 40. Whole-exome sequencing (WES) was conducted on genomic DNA extracted from peripheral blood cells. As a result, 3,481 single nucleotide variants were identified. By bioinformatical tools and the published gene list associated with genetic predisposition of cancer, pathogenic variants were detected in ten germline genes: ATR, FANCD2, FANCE, GATA2, HFE, MSH2, PDGFRA, PMS2, SDHB, and WAS. Patients with pathogenic variants were more likely to occur in females (9/10, 90.0%) and have stage IV lung adenocarcinoma (4/10, 40%). Furthermore, germline mutations in 17 genes (ASB18, B3GALT5, CLEC4F, COL6A6, CYP4B1, C6orf132, EXO1, GATA4, HCK, KCP, NPHP4, PIGX, PPIL2, PPP1R3G, RRBP1, SALL4, and TTC28), which occurred in at least two patients, displayed potentially pathogenic effects. Gene ontology analysis further showed that these genes with germline mutations were mainly located in nucleoplasm and associated with DNA repair-related biological processes. The study provides spectrum of pathogenic variants and functional explanation for genetic predisposition of lung adenocarcinoma in young never-smokers, which sheds a light on prevention and early diagnosis of lung cancer.

04 Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

多基因罕见变异ALS患者

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DOI：

https://doi.org/10.1007/s43657-022-00093-8

引用格式：

Dong, S., Yin, X., Wang, K. et al. Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis. Phenomics 3, 167–181 (2023). https://doi.org/10.1007/s43657-022-00093-8

该研究对来自华东地区的57例sALS患者和5个fALS家系的43个相关基因进行分析，共在16个不同基因上检测出30个罕见突变位点。研究进一步证实ALS患者可携带多个与ALS相关的突变位点，且携带罕见突变与其生存期相关。研究结果表明，无论是散发性还是家族性ALS患者，携带罕见突变都可能对其预后产生不利影响，从而进一步为ALS的“寡基因遗传”理论提供了证据支持。

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity. Recent studies have suggested an oligogenic basis of ALS, in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects. To assess the contribution of possible oligogenic inheritance, we profiled a panel of 43 relevant genes in 57 sporadic ALS (sALS) patients and eight familial ALS (fALS) patients from five pedigrees in east China. We filtered rare variants using the combination of the Exome Aggregation Consortium, the 1000 Genomes and the HuaBiao Project. We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype correlation. Overall, we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes, among which two sALS and four fALS patients harbored two or more variants. Of note, the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants. Typically, in one fALS pedigree with three variants, the family member with three variants (Superoxide dismutase 1 (SOD1) p.V48A, Optineurin (OPTN) p.A433V and TANK binding kinase 1 (TBK1) p.R573H) exhibited much more severe disease phenotype than the member carrying one variant (TBK1 p.R573H). Our findings suggest that rare variants could exert a negative prognostic effect, thereby supporting the oligogenic inheritance of ALS.

05 Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression

基于Data Independent Acquisition-Mass Spectrometry(DIA-MS)的淋巴瘤临床蛋白质组学分析

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DOI：

https://doi.org/10.1007/s43657-022-00075-w

引用格式：

Ku, X., Wang, J., Li, H. et al. Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression. Phenomics 3, 148–166 (2023). https://doi.org/10.1007/s43657-022-00075-w

淋巴结中蛋白质组的改变通常表明异常的信号通路可能与各种淋巴疾病有关。目前用于淋巴瘤组织学分类的临床生物标志物有许多差异，特别是对于边缘病例。因此，他们开展了一项全面的蛋白质组学研究，旨在建立各种淋巴疾病患者的蛋白质组学景观，并确定与不同疾病亚组相关的蛋白质组学变异。在这项研究中，109例来自各种淋巴疾病(重点是非霍奇金淋巴瘤)患者的新鲜冷冻淋巴结组织采用数据独立获取质谱法进行分析。定量的蛋白质组学景观被全面表征以鉴定每个亚群的特征蛋白谱。研究还探讨了临床结果与特征蛋白表达谱之间的潜在相关性。两个代表性的特征蛋白，磷脂结合蛋白Annexin A6 (ANXA6)和磷脂酶C γ 2 (PLCG2)，通过免疫组织化学成功验证。他们还评估了获得的蛋白质组学特征分离多种淋巴异常的能力，并鉴定了几个核心特征蛋白，如唾液酸结合Ig样凝集素1 (SIGLEC1)和免疫相关蛋白5 (GIMAP5)的GTPase。

Abstract

An altered proteome in lymph nodes often suggests abnormal signaling pathways that may be associated with diverse lymphatic disorders. Current clinical biomarkers for histological classification of lymphomas have encountered many discrepancies, particularly for borderline cases. Therefore, we launched a comprehensive proteomic study aimed to establish a proteomic landscape of patients with various lymphatic disorders and identify proteomic variations associated with different disease subgroups. In this study, 109 fresh-frozen lymph node tissues from patients with various lymphatic disorders (with a focus on Non-Hodgkin’s Lymphoma) were analyzed by data-independent acquisition mass spectrometry. A quantitative proteomic landscape was comprehensively characterized, leading to the identification of featured protein profiles for each subgroup. Potential correlations between clinical outcomes and expression profiles of signature proteins were also probed. Two representative signature proteins, phospholipid-binding proteins Annexin A6 (ANXA6) and Phospholipase C Gamma 2 (PLCG2), were successfully validated via immunohistochemistry. We also evaluated the capability of acquired proteomic signatures to segregate multiple lymphatic abnormalities and identified several core signature proteins, such as Sialic Acid Binding Ig Like Lectin 1 (SIGLEC1) and GTPase of immunity-associated protein 5 (GIMAP5). In summary, the established lympho-specific data resource provides a comprehensive map of protein expression in lymph nodes during multiple disease states, thus extending the existing human tissue proteome atlas. Our findings will be of great value in exploring protein expression and regulation underlying lymphatic malignancies, while also providing novel protein candidates to classify various lymphomas for more precise medical practice.

06 Cross-sectional Exploration of the Relationship Between Glutamate Abnormalities and Tic Disorder Severity Using Proton Magnetic Resonance Spectroscopy

TD受试者左侧纹状体1H-MRS结果具有代表

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DOI：

https://doi.org/10.1007/s43657-022-00064-z

引用格式：

Hao, J., Zhang, X., Liu, Y. et al. Cross-sectional Exploration of the Relationship Between Glutamate Abnormalities and Tic Disorder Severity Using Proton Magnetic Resonance Spectroscopy. Phenomics 3, 138–147 (2023). https://doi.org/10.1007/s43657-022-00064-z

谷氨酸(Glu)已被报道与抽动障碍(TD)的病理生理密切相关。该研究对年龄在5-13岁之间的无药TD患者和健康对照进行了横断面研究。首先，他们测量了患者和对照组的Glu水平，并观察了亚组的差异，包括轻度TD患者和中度TD患者。然后检查了Glu水平与患者临床特征之间的相关性。最后评价1H-MRS的诊断价值及影响因素。研究结果显示，所有TD患者纹状体中的Glu水平与健康对照组无显著差异。亚组分析显示，中度TD组Glu水平高于轻度TD组和健康对照组。相关分析显示，Glu水平与TD严重程度呈显著正相关。Glu水平区分轻度抽搐和中度抽搐的最佳临界值为1.244，敏感性为88.2%，特异性为94.7%。多元线性回归模型显示，TD的严重程度是影响Glu水平的重要因素之一。该研究发现Glu水平主要与抽搐的严重程度相关，因此它可以作为TD分类的关键生物标志物。

Abstract

Glutamate (Glu) has been reported to be closely related to the pathophysiology of Tic Disorders (TD). By using proton magnetic resonance spectroscopy (1H-MRS), we aimed to investigate the relationship between in vivo Glu levels and the severity of TD. We performed a cross-sectional study in medication-free patients with TD and healthy controls aged between 5 and 13 years using 1H-MRS at 3 T. First, we measured the Glu levels in both patients and controls and observed the difference in subgroups, including mild TD patients and moderate TD patients. We then examined the correlations between the Glu levels and clinical features of the patients. Finally, we assessed the diagnostic value of 1H-MRS and the influencing factors. Our results show that the Glu levels in the striatum of all patients with TD were not significantly different from those of the healthy controls. Subgroup analysis revealed that the Glu levels in the moderate TD group were higher than those in the mild TD group and healthy controls. The correlation analysis showed that Glu levels are strongly positive correlated with TD severity. The optimal cutoff value of Glu levels to differentiate mild tics from moderate tics was 1.244, with a sensitivity of 88.2% and a specificity of 94.7%. Multiple linear regression models revealed that the severity of TD is one of the important factors that affect Glu levels. We conclude that Glu levels are mainly associated with the severity of tics, thus it could serve as a key biomarker for TD classification.

07 In Silico Pipeline to Identify Tumor-Specific Antigens for Cancer Immunotherapy Using Exome Sequencing Data

肿瘤疫苗中肿瘤抗原的鉴定

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DOI：

https://doi.org/10.1007/s43657-022-00084-9

引用格式：

Morazán-Fernández, D., Mora, J. & Molina-Mora, J.A. In Silico Pipeline to Identify Tumor-Specific Antigens for Cancer Immunotherapy Using Exome Sequencing Data. Phenomics 3, 130–137 (2023). https://doi.org/10.1007/s43657-022-00084-9

该文提出了一个生物信息学方面的操作手册，以检测肿瘤组织中与单核苷酸变异（SNVs）或与突变相关的肿瘤特异性抗原。该研究使用公开的数据来建立模型，这包括从一个病例中获得的结直肠癌和健康细胞的外显子测序数据，以及特定人群中频繁出现的人类白细胞抗原（HLA）I类等位基因。HLA数据样本来源于哥斯达黎加中央山谷人群。在该研究的模型数据中，作者发现了28个非沉默的SNVs，存在于一号染色体的17个基因中。该操作流程发现了23个强结合肽，这些强结合肽来自于哥斯达黎加人口经常出现的HLA I类等位基因的SNVs。该研究是首个在HLA等位基因背景下利用DNA测序数据进行的癌症疫苗研究。研究表明，标准化的操作手册不仅能够识别特定的新抗原，而且还为使用最佳生物信息学实践最终设计癌症疫苗提供了一个完整的流程。

Abstract

Tumor-specific antigens or neoantigens are peptides that are expressed only in cancer cells and not in healthy cells. Some of these molecules can induce an immune response, and therefore, their use in immunotherapeutic strategies based on cancer vaccines has been extensively explored. Studies based on these approaches have been triggered by the current high-throughput DNA sequencing technologies. However, there is no universal nor straightforward bioinformatic protocol to discover neoantigens using DNA sequencing data. Thus, we propose a bioinformatic protocol to detect tumor-specific antigens associated with single nucleotide variants (SNVs) or “mutations” in tumoral tissues. For this purpose, we used publicly available data to build our model, including exome sequencing data from colorectal cancer and healthy cells obtained from a single case, as well as frequent human leukocyte antigen (HLA) class I alleles in a specific population. HLA data from Costa Rican Central Valley population was selected as an example. The strategy included three main steps: (1) pre-processing of sequencing data; (2) variant calling analysis to detect tumor-specific SNVs in comparison with healthy tissue; and (3) prediction and characterization of peptides (protein fragments, the tumor-specific antigens) derived from the variants, in the context of their affinity with frequent alleles of the selected population. In our model data, we found 28 non-silent SNVs, present in 17 genes in chromosome one. The protocol yielded 23 strong binders peptides derived from the SNVs for frequent HLA class I alleles for the Costa Rican population. Although the analyses were performed as an example to implement the pipeline, to our knowledge, this is the first study of an in silico cancer vaccine using DNA sequencing data in the context of the HLA alleles. It is concluded that the standardized protocol was not only able to identify neoantigens in a specific but also provides a complete pipeline for the eventual design of cancer vaccines using the best bioinformatic practices.

08 Autophagic Clearance of Lipid Droplets Alters Metabolic Phenotypes in a Genetic Obesity–Diabetes Mouse Model

自噬清除LDs改变db/db小鼠模型的代谢表

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DOI：

https://doi.org/10.1007/s43657-022-00080-z

引用格式：

Chen, N., Lu, B. & Fu, Y. Autophagic Clearance of Lipid Droplets Alters Metabolic Phenotypes in a Genetic Obesity–Diabetes Mouse Model. Phenomics 3, 119–129 (2023). https://doi.org/10.1007/s43657-022-00080-z

该研究验证了LD·ATTECs对db/db小鼠模型代谢表型的影响，描述了LD·ATTECs在肥胖-糖尿病小鼠模型中改善的代谢表型，如增加氧气摄入和二氧化碳释放，增加热量产生，并在黑暗阶段略微增强运动，降低血糖水平和改善胰岛素敏感性。总之，该研究从表型角度揭示了脂滴自噬清除在肥胖-糖尿病发病机制中新的功能影响。

Abstract

Lipid droplets (LDs) are intracellular organelles that store neutral lipids, and their aberrant accumulation is associated with many diseases including metabolic disorders such as obesity and diabetes. Meanwhile, the potential pathological contributions of LDs in these diseases are unclear, likely due to a lack of chemical biology tools to clear LDs. We recently developed LD-clearance small molecule compounds, Lipid Droplets·AuTophagy TEthering Compounds (LD·ATTECs), that are able to induce autophagic clearance of LDs in cells and in the liver of db/db (C57BL/6J Leprdb/Leprdb) mouse model, which is a widely used genetic model for obesity–diabetes. Meanwhile, the potential effects on the metabolic phenotype remain to be elucidated. Here, using the metabolic cage assay and the blood glucose assay, we performed phenotypic characterization of the effects of the autophagic degradation of LDs by LD·ATTECs in the db/db mouse model. The study reveals that LD·ATTECs increased the oxygen uptake of mice and the release of carbon dioxide, enhanced the heat production of animals, partially enhanced the exercise during the dark phase, decreased the blood glucose level and improved insulin sensitivity. Collectively, the study characterized the metabolic phenotypes induced by LD·ATTECs in an obesity–diabetes mouse model, revealing novel functional impacts of autophagic clearance of LDs and providing insights into LD biology and obesity–diabetes pathogenesis from the phenotypic perspective.

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