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Rare variants at KCNJ2 are associated with LDL-cholesterol levels in a cross-population study. 在一项跨人群研究中,KCNJ2 的罕见变异与低密度脂蛋白胆固醇水平有关。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-06-28 DOI: 10.1038/s41525-024-00417-9
Niccolò Rossi, Najeeb Syed, Alessia Visconti, Elbay Aliyev, Sarah Berry, Mafalda Bourbon, Tim D Spector, Pirro G Hysi, Khalid A Fakhro, Mario Falchi

Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10-12) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.

我们利用英国 1751 名受试者和卡塔尔 2587 名受试者的全基因组测序数据,发现绘制在酸味相关基因 KCNJ2 上的罕见变异与低密度脂蛋白胆固醇(LDL-C,P = 2.10 × 10-12)降低以及膳食反式脂肪摄入量减少 22% 有关。这项研究发现了一个新的低密度脂蛋白胆固醇候选罕见基因座,为了解心血管疾病的复杂性状的遗传结构提供了新的视角。
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引用次数: 0
Structure and transcription of integrated HPV DNA in vulvar carcinomas. 外阴癌中整合 HPV DNA 的结构和转录。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-06-19 DOI: 10.1038/s41525-024-00418-8
Anne Van Arsdale, Lauren Turker, Yoke-Chen Chang, Joshua Gould, Bryan Harmon, Elaine C Maggi, Olga Meshcheryakova, Maxwell P Brown, Dana Luong, Koenraad Van Doorslaer, Mark H Einstein, Dennis Y S Kuo, Deyou Zheng, Brian J Haas, Jack Lenz, Cristina Montagna

HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.

部分外阴癌与人乳头瘤病毒感染有关。通过杂交捕获和 DNA 测序,13 例外阴癌中有 5 例检测到了 HPV DNA。在这五例中,有三例将HPV16 DNA整合到了人类DNA中。这些插入物位于人类 NCKAP1、C5orf67 和 LRP1B 的内含子中。NCKAP1和C5orf67中的整合片段两侧是人类DNA中的短直接重复序列,这与HPV DNA插入到中止、交错、核酸内切的位点是一致的。C5orf67 中的插入物是一个 36 kbp 的人类-HPV-异源-癌变 DNA,要么是染色体外的环状结构,要么是人类基因组内的串联重复。人类环化/重复交界处是以单核苷酸分辨率确定的。整合后的病毒 DNA 片段都保留了完整的上游调控区以及邻近的病毒 E6 和 E7 致癌基因。RNA 测序显示,从整合的病毒 DNA 中持续转录的 HPV 基因只有 E7 和 E6*I。另外两个HPV DNA+肿瘤有合并感染,但没有整合的证据。HPV阳性和HPV阴性外阴癌表现出截然不同的人类全基因表达模式,这与之前观察到的HPV阳性和HPV阴性宫颈癌和口咽癌之间的差异部分重叠。大部分差异表达基因涉及免疫系统功能。因此,外阴癌的转录和 HPV DNA 整合与其他 HPV 阳性癌症相似。这项研究强调了杂交捕获技术与DNA和RNA测序技术相结合在确定广泛的HPV类型、确定病毒DNA的人类基因组整合状态以及阐明其结构方面的威力。
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引用次数: 0
Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease. 川崎病冠状动脉对静脉注射丙种球蛋白反应的药物基因组学。
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-30 DOI: 10.1038/s41525-024-00419-7
Sadeep Shrestha, Howard W Wiener, Sabrina Chowdhury, Hidemi Kajimoto, Vinodh Srinivasasainagendra, Olga A Mamaeva, Ujval N Brahmbhatt, Dolena Ledee, Yung R Lau, Luz A Padilla, Jake Y Chen, Nagib Dahdah, Hemant K Tiwari, Michael A Portman

Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

川崎病(KD)是一种婴幼儿多系统炎症性疾病,可导致急性血管炎。尽管接受了静脉注射丙种球蛋白(IVIG)治疗,但 KD 冠状动脉瘤(CAA)的发病机制尚不清楚。我们对接受 IVIG 治疗的不同种族 KD 患者队列进行了全基因组测序(WGS)关联分析,分析均采用 AHA 指南。我们将冠状动脉瘤(CAA)(N = 234)定义为冠状动脉z≥2.5,将大冠状动脉瘤(CAA/L)(N = 92)定义为z≥5.0。我们使用加法模型,在病例和 238 例无 CAA 的对照组之间建立了逻辑回归模型,以检验基因变异与急性 KD 期间 CAA/L 以及与持续 >6 周的关系。我们对年龄、性别和遗传祖先的三个主成分进行了调整。与 CAA/L 相关的最重要变异位于基因间区(rs62154092 p
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引用次数: 0
An efficient molecular genetic testing strategy for incontinentia pigmenti based on single-tube long fragment read sequencing. 基于单管长片段读取测序的猪尿失禁高效分子遗传检测策略。
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-29 DOI: 10.1038/s41525-024-00421-z
Min Chen, Mei-Hua Tan, Jiao Liu, Yan-Mei Yang, Jia-Ling Yu, Li-Juan He, Ying-Zhi Huang, Yi-Xi Sun, Ye-Qing Qian, Kai Yan, Min-Yue Dong

Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG△4-10 deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG△4-10 deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.

猪失禁症(IP)是一种罕见的X连锁显性神经外胚层发育不良症,主要影响女性。唯一已知的致病基因是IKBKG,最常见的遗传原因是两个MER67B重复序列之间的重组导致IKBKG△4-10缺失。由于存在一个高度同源的非致病假基因IKBKGP1,因此检测IKBKG的变异具有挑战性。在本研究中,我们采用基于单管长片段读数(stLFR)测序的策略和专门的分析流水线,在四名 IP 患者中成功鉴定出了四个致病变体。其中发现了三个帧移变异(c.519-3_519dupCAGG、c.1167dupC 和 c.700dupT),随后通过桑格测序进行了验证。值得注意的是,c.519-3_519dupCAGG 在 IKBKG 和 IKBKGP1 中都被发现,而其他两个变异只在功能基因中被检测到。在一名患者中发现并证实了IKBKG△4-10缺失。这些结果表明,所提出的策略可以识别潜在的致病变体,并区分它们是来自于IKBKG还是其假基因。因此,这种策略可以成为一种有效的 IKBKG 基因检测方法。通过对全基因组的全面了解,该方法还能探索与 IP 潜在相关的其他基因。此外,该策略还能帮助人们深入了解因假基因而导致检测困难的其他疾病。
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引用次数: 0
Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients. 分析细胞游离 DNA 预测结直肠癌患者贝伐珠单抗治疗效果
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-29 DOI: 10.1038/s41525-024-00415-x
Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.

为了预测贝伐单抗(BVZ)联合疗法的疗效,我们采用了无细胞DNA(cfDNA)来测定转移性结直肠癌(mCRC)患者的染色体不稳定性(CIN)、核糖体足迹(NF)和甲基化图谱。低覆盖率全基因组测序(LC-WGS)是从 AC-ANGIOPREDICT II 期试验(NCT01822444)中收集的 74 例 mCRC 患者的匹配肿瘤和血浆样本中进行的,并对 CIN 和 NF 进行了分析。曼海姆大学医学中心(UMM)的验证队列血浆样本也进行了类似分析。在 BVZ 治疗前和治疗后收集的 61 份 AC-ANGIOPREDICT 血浆样本被选中进行靶向甲基化测序。利用 cfDNA CIN 图谱,AC-ANGIOPREDICT 样本以 92.3% 的准确率被亚型为低 CIN 和高 CIN 群组,并观察到匹配血浆和肿瘤之间具有良好的一致性。据观察,CIN 高的患者生存率有所提高。基于血浆的CIN分类在UMM队列中得到了验证。甲基化分析确定了低CIN与高CIN的差异(AUC = 0.87)。此外,BVZ 后甲基化评分的明显降低与预后的改善有关(p = 0.013)。分析血浆样本中 cfDNA 的 CIN、NFs 和甲基化图谱有助于对 CIN 群组进行分层,从而为患者的治疗反应提供依据。
{"title":"Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.","authors":"Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne","doi":"10.1038/s41525-024-00415-x","DOIUrl":"10.1038/s41525-024-00415-x","url":null,"abstract":"<p><p>To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"33"},"PeriodicalIF":5.3,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease. 基于结构的网络分析预测了与遗传性视网膜疾病相关的人类蛋白质中的致病变体。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-27 DOI: 10.1038/s41525-024-00416-w
Blake M Hauser, Yuyang Luo, Anusha Nathan, Ahmad Al-Moujahed, Demetrios G Vavvas, Jason Comander, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Gaurav D Gaiha, Elizabeth J Rossin

Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.

基因测序技术的进步加快了基因变异的鉴定速度,但还需要更好的工具来了解哪些基因变异是致病因素。这在基因治疗是一种潜在的致病变异治疗方法的领域尤其有用,如遗传性视网膜病(IRD)。在这里,我们应用基于结构的网络分析(SBNA)来识别病毒蛋白质中受变异约束的氨基酸残基,该方法已成功用于识别发生错义突变时可能导致 IRD 的残基。SBNA 完全基于结构第一性原理,并不与特定结果数据相匹配,这使其有别于其他当代的错义预测工具。在具有高质量结构数据的 4 个研究充分的人类疾病相关蛋白(BRCA1、HRAS、PTEN 和 ERK2)中,我们发现 SBNA 分数与深度诱变数据密切相关。当应用于 47 个具有高质量晶体结构数据的 IRD 基因时,根据 ClinVar 数据库中的表型定义,SBNA 评分可靠地鉴定出了致病变体。最后,我们将这种方法应用于马萨诸塞眼耳科(MEE)的 63 名 IRD 患者,这些患者的遗传病因尚未确定。使用 IRD 相关基因的 SBNA 评分和 BLOSUM62 评分建立的未训练模型成功预测了新型变异体的致病性(AUC = 0.851),使我们能够确定 40 例 IRD 患者中可能的致病变异体。基于进化多序列比对的 EVE 评分(AUC = 0.927)纳入了正交数据,进一步提高了模型性能。总之,SBNA 可用于成功识别人类蛋白质中的致病变异,并有助于以无偏见的方式预测 IRD 的致病变异。
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引用次数: 0
Evaluating the utility of multi-gene, multi-disease population-based panel testing accounting for uncertainty in penetrance estimates. 评估基于人群的多基因、多疾病面板测试的效用,考虑渗透率估算的不确定性。
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-17 DOI: 10.1038/s41525-024-00414-y
Jane W Liang, Kurt D Christensen, Robert C Green, Peter Kraft

Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.

群体种系检测可以有效地检测出多种疾病的有害变异,但识别这些变异的利弊并不总是很清楚。我们提出了一种多基因、多疾病的综合效用公式,让用户可以根据变异频率、估计渗透率以及检测阳性但未发病和检测阴性但发病的主观效用,考虑添加或删除面板中的每个基因。我们提供了效用的可信区间,以反映渗透率估计值的不确定性。即使考虑到参数估计的不确定性,罕见的高穿透性致畸变异体也倾向于为各种用户指定的不安全性贡献正的净效用。然而,渗透性中等、不确定的致畸变异的临床效用更多地取决于假定的不确定性。决定是否将某个基因纳入研究小组取决于变异频率、渗透率和主观效用,并应考虑到这些因素的不确定性。
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引用次数: 0
Reply to: Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects 答复人体 OPN1LW-OPN1MW 基因簇遗传测试中的陷阱
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-04 DOI: 10.1038/s41525-024-00409-9
Lonneke Haer-Wigman, Amber den Ouden, Ronny Derks, Maria M. van Genderen, Dorien Lugtenberg, Joke Verheij, Raymon Vijzelaar, Helger G. Yntema, Lisenka E. L. M. Vissers, Kornelia Neveling
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引用次数: 0
Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects 人体 OPN1LW-OPN1MW 基因簇遗传测试中的陷阱
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-05-04 DOI: 10.1038/s41525-024-00406-y
Bernd Wissinger, Britta Baumann, Elena Buena-Atienza, Caspar Gross, Susanne Kohl
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引用次数: 0
Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions 解决超罕见遗传病描述差距的共识报告指南
IF 5.3 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-04-06 DOI: 10.1038/s41525-024-00408-w
Ali AlMail, Ahmed Jamjoom, Amy Pan, Min Yi Feng, Vann Chau, Alissa M. D’Gama, Katherine Howell, Nicole S. Y. Liang, Amy McTague, Annapurna Poduri, Kimberly Wiltrout, Anne S. Bassett, John Christodoulou, Lucie Dupuis, Peter Gill, Tess Levy, Paige Siper, Zornitza Stark, Jacob A. S. Vorstman, Catherine Diskin, Natalie Jewitt, Danielle Baribeau, Gregory Costain

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

全基因组测序和基因匹配服务正在推动一个以基因型为导向确定新型遗传病的新时代。在以发现为重点的研究中,报告的表型数据在多大程度上满足了临床医生和家庭的信息需求尚不清楚。我们确定了 2017 年至 2021 年期间在 10 种遗传学期刊上发表的新型孟德尔疾病报告。我们通过与以下六个优先领域相关的 46 个问题对表型数据的质量和细节进行了评判:(I) 发育、认知和心理健康;(II) 喂养和生长;(III) 药物使用和治疗史;(IV) 疼痛、睡眠和生活质量;(V) 成年期;以及 (VI) 癫痫。对于一部分文章,所有后续发表的随访病例描述都以类似的方式进行了识别和评估。在四个国家的内容专家的参与下,我们采用了改良的德尔菲法来制定共识报告指南。在筛选出的 3243 篇文章中,共有 200 篇符合纳入标准。87%的论文对6个领域中每个领域的相关表型细节的评价为肤浅或不足。例如,只有不到 10% 的论文提供了有关神经精神诊断和 "行为问题 "的详细信息,或有关喂养问题类型/性质的详细信息。后续报告(n = 95)很少提供额外的表型数据。总之,对于许多新描述的遗传病,缺乏与临床管理、遗传咨询以及患者和家属所陈述的优先事项相关的表型信息。PHELIX(PHEnotype LIsting fiX)报告指南核对表的开发旨在改善基因组时代的表型报告。
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引用次数: 0
期刊
NPJ Genomic Medicine
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