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Adaptive evolution of SARS-CoV-2 during a persistent infection for 521 days in an immunocompromised patient. 免疫功能低下患者持续感染521天期间SARS-CoV-2的适应性进化
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-17 DOI: 10.1038/s41525-025-00463-x
Hanno Schmidt, Lea Schick, Jürgen Podlech, Angélique Renzaho, Bettina Lieb, Stefan Diederich, Thomas Hankeln, Bodo Plachter, Oliver Kriege

Immunocompromised patients struggle to adequately clear viral infections, offering the virus the opportunity to adapt to the immune system in the host. Here we present a case study of a patient undergoing allogeneic hematopoietic stem cell transplantation with a 521-day follow-up of a SARS-CoV-2 infection with the BF.7.21 variant. Virus samples from five time points were submitted to whole genome sequencing. Between the first detection of SARS-CoV-2 infection and its clearance, the patient's virus population acquired 34 amino acid substitutions and 8 deletions in coding regions. With 11 amino acid substitutions in the receptor binding domain of the virus' spike protein, substitutions were 15 times more abundant than expected for a random distribution in this highly functional region. Amongst them were the substitutions S:K417T, S:N440S, S:K444R, S:V445A, S:G446N, S:L452Q, S:N460K, and S:E484V at positions that are notorious for their resistance-mediating effects. The substitution patterns found indicate ongoing adaptive evolution.

免疫功能低下的患者很难充分清除病毒感染,这给病毒提供了适应宿主免疫系统的机会。在这里,我们提出了一个接受同种异体造血干细胞移植的患者的病例研究,并对感染BF.7.21变体的SARS-CoV-2感染进行了521天的随访。五个时间点的病毒样本进行全基因组测序。从首次检测到SARS-CoV-2感染到其被清除,患者的病毒种群在编码区发生了34个氨基酸替换和8个缺失。在病毒刺突蛋白的受体结合区域有11个氨基酸取代,取代量比在这个高功能区域随机分布的预期多15倍。其中包括S:K417T, S:N440S, S:K444R, S:V445A, S:G446N, S:L452Q, S:N460K和S:E484V在以其电阻介导作用而闻名的位置上的取代。发现的替代模式表明正在进行的适应性进化。
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引用次数: 0
Germline structural variant as the cause of Lynch Syndrome in a family from Ecuador. 种系结构变异是厄瓜多尔一个家庭林奇综合征的病因。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-17 DOI: 10.1038/s41525-025-00462-y
Gemma Llargués-Sistac, Laia Bonjoch, Jenifer Muñoz, Xavier Domínguez-Rovira, Teresa Ocaña, Maria Isabel Alvarez-Mora, Celia Badenas, Anna Esteve-Codina, Carlos Reyes-Silva, Gabriela Jaramillo-Koupermann, Maria Teresa Rodrigo, Sandra López-Prades, Miriam Cuatrecasas, Antoni Castells, Francesc Balaguer, Leticia Moreira, Guerau Fernandez, Sergi Castellví-Bel

Colorectal cancer (CRC) is one of the most common cancers worldwide. Lynch Syndrome (LS) is the most common form of hereditary CRC and it is caused by germline defects in the DNA-mismatch repair (MMR) pathway. It is of extreme importance for affected LS patients and their relatives to identify the germline causative alteration to provide intensified surveillance to those at risk and allow early diagnosis and cancer prevention. Current approaches for LS molecular diagnosis typically involve screening of the MMR genes by targeted gene-panel sequencing and rearrangement screening. We report the identification and characterization of a novel germline structural variant encompassing 48.757 kb, involving the 3'-ends of the MLH1 and LRRFIP2 genes, as the cause of LS in a family of Ecuador. Whole-genome sequencing and transcriptomics allowed the identification of the genomic rearrangement and highlights the importance of the use of these additional approaches to achieve a comprehensive molecular diagnosis in some LS patients.

结直肠癌(CRC)是世界上最常见的癌症之一。Lynch综合征(LS)是遗传性结直肠癌最常见的形式,它是由dna错配修复(MMR)途径中的种系缺陷引起的。鉴别LS患者及其亲属的种系致病改变,对高危人群进行强化监测,实现早期诊断和癌症预防,具有极其重要的意义。目前的LS分子诊断方法通常包括通过靶向基因面板测序和重排筛选筛选MMR基因。我们在厄瓜多尔的一个家庭中发现了一种新的种系结构变异,全长48757 kb,涉及MLH1和LRRFIP2基因的3'端,是导致LS的原因。全基因组测序和转录组学允许鉴定基因组重排,并强调了使用这些附加方法在一些LS患者中实现全面分子诊断的重要性。
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引用次数: 0
Pre-T cell receptor-α immunodeficiency detected exclusively using whole genome sequencing. 利用全基因组测序技术检测前t细胞受体-α免疫缺陷。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-13 DOI: 10.1038/s41525-024-00453-5
Daniele Merico, Nigel Sharfe, Harjit Dadi, Bhooma Thiruvahindrapuram, Jill de Rijke, Zakia Dahi, Mehdi Zarrei, Abdulrahman Al Ghamdi, Azhar Al Shaqaq, Linda Vong, Stephen W Scherer, Chaim M Roifman

Maturation of αβ lineage T cells in the thymus relies on the formation and cell surface expression of a pre-T cell receptor (TCR) complex, composed of TCRβ chain and pre-TCRα (pTCRα) chain heterodimers, giving rise to a diverse T cell repertoire. Genetic aberrations in key molecules involved in T cell development lead to profound T cell immunodeficiency. Definitive genetic diagnosis guides treatment choices and counseling. In this study, we describe the role of whole genome sequencing (WGS) in providing a definitive diagnosis for a child with T cell deficiency, where targeted panel sequencing of SCID genes and whole exome sequencing had failed. A novel homozygous 8kb deletion in PTCRA, encoding pTCRα, was identified. To date, use of WGS remains restricted and for many geographical regions, is clinically unavailable.

胸腺中αβ谱系T细胞的成熟依赖于由TCRβ链和TCRα (pTCRα)链异源二聚体组成的T细胞前受体(TCR)复合物的形成和细胞表面表达,从而产生多样化的T细胞库。参与T细胞发育的关键分子的遗传畸变导致T细胞严重免疫缺陷。明确的基因诊断指导治疗选择和咨询。在这项研究中,我们描述了全基因组测序(WGS)在为患有T细胞缺乏症的儿童提供明确诊断中的作用,其中SCID基因的靶向小组测序和全外显子组测序都失败了。在PTCRA中发现了一个新的8kb纯合子缺失,编码pTCRα。迄今为止,WGS的使用仍然受到限制,在许多地理区域,临床无法使用。
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引用次数: 0
Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing. 通过综合种系和肿瘤测序评估候选高级别浆液性卵巢癌易感基因。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-10 DOI: 10.1038/s41525-024-00447-3
Deepak N Subramanian, Maia Zethoven, Kathleen I Pishas, Evanny R Marinović, Simone McInerny, Simone M Rowley, Prue E Allan, Lisa Devereux, Dane Cheasley, Paul A James, Ian G Campbell

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

高级别浆液性卵巢癌(HGSOC)具有显著的遗传成分,但只有一半是可以解释的。之前,我们对BRCA1和brca2阴性的HGSOC患者进行了种系外显子组测序,揭示了3个建议的和43个新的候选基因,这些基因富含罕见的功能丧失变体。为了验证,我们使用无病对照的基因组数据进行了病例对照分析。这证实了几乎所有先前鉴定的基因都富集。此外,来自变异携带者的111个HGSOC肿瘤与其他补充研究一起测序,寻找双等位基因失活的证据作为支持证据。PALB2和ATM被证实为HGSOC易感基因,6/8种系载体肿瘤表现出双等位基因失活并伴有特征性突变特征。在候选基因中,只有LLGL2一致表现出双等位基因失活和蛋白表达缺失,支持其作为新的HGSOC易感基因。剩下的候选基因无法验证。因此,将病例对照分析与肿瘤测序相结合对于家族性癌症研究中精确的基因发现至关重要。
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引用次数: 0
Author Correction: The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort. 作者更正:自闭症谱系障碍的遗传景观在一个祖先多样化的队列。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-26 DOI: 10.1038/s41525-024-00458-0
Ashlesha Gogate, Kiran Kaur, Raida Khalil, Mahmoud Bashtawi, Mary Ann Morris, Kimberly Goodspeed, Patricia Evans, Maria H Chahrour
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引用次数: 0
Clinical and genetic characterization of patients with late onset Wilson's disease. 迟发性威尔逊氏病患者的临床和遗传特征
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-24 DOI: 10.1038/s41525-024-00459-z
Wenming Yang, Yue Yang, Han Wang, Jiuxiang Wang, Shijie Zhang

Wilson's disease (WD) typically manifests in children and young adults, with little knowledge of its late-onset forms. In this study, we performed a retrospective cohort study of 105 WD patients (99 index cases, 6 siblings) with an onset age ≥35 years. We compared 99 index late-onset patients with 1237 early-onset patients and analyzed the ATP7B variant penetrance referring to the Genome Aggregation Database (gnomAD). Sixty-two ATP7B variants were identified in the late-onset patients, among which A874V, V1106I, R919G, and T935M were correlated with late presentation of WD. Regarding gnomAD, V1106I and T935M exhibited significantly low penetrance, and there is a lack of patients carrying a genotype of V1106I/V1106I, R919G/R919G, T935M/T935M, V1106I/T935M, V1106I/R919G, or T935M/R919G. Our data revealed that patients carrying a combination of two late-onset variants may be overlooked due to atypical or lack of WD symptoms, which may provide valuable insights into the genetic basis and diagnosis of WD.

威尔逊氏病(WD)通常表现在儿童和年轻人,很少了解其晚发形式。在这项研究中,我们对105例发病年龄≥35岁的WD患者(99例指数病例,6例兄弟姐妹)进行了回顾性队列研究。我们比较了99例指数迟发性患者和1237例早发性患者,并参考基因组聚集数据库(gnomAD)分析了ATP7B变异外显率。在晚发患者中鉴定出62种ATP7B变异,其中A874V、V1106I、R919G和T935M与WD的晚期表现相关。在gnomAD中,V1106I和T935M的外显率明显较低,缺乏携带V1106I/V1106I、R919G/R919G、T935M/T935M、V1106I/T935M、V1106I/R919G或T935M/R919G基因型的患者。我们的数据显示,由于不典型或缺乏WD症状,携带两种晚发性变异组合的患者可能被忽视,这可能为WD的遗传基础和诊断提供有价值的见解。
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引用次数: 0
Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts. 通过对人类肾囊肿进行深度测序发现常染色体显性多囊肾的体细胞突变。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00452-6
Amali C Mallawaarachchi, Yvonne Hort, Laura Wedd, Kitty Lo, Sarah Senum, Mojgan Toumari, Wenhan Chen, Mike Utsiwegota, Jane Mawson, Scott Leslie, Jerome Laurence, Lyndal Anderson, Paul Snelling, Robert Salomon, Gopala K Rangan, Timothy Furlong, John Shine, Mark J Cowley

Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation. We used unique molecular identifiers, high-depth massively parallel sequencing and custom analysis techniques to identify somatic second-hit mutations in 24 whole cysts from disparate regions of six human ADPKD kidneys, utilising replicate samples and orthogonal confirmation. Average depth of coverage of 1166 error-corrected reads for PKD1 and 539 reads for PKD2 was obtained. 58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant. We demonstrate that low-frequency somatic mutations are detectable in a proportion of cysts from end-stage ADPKD human kidneys. Further studies are required to understand the drivers of this somatic mutation.

常染色体显性多囊肾病(ADPKD)导致进行性囊肿,导致肾衰竭,是由PKD1或PKD2的杂合种系变异引起的。囊肿的发病机制尚不明确。体细胞二次撞击突变与囊肿发病有关,但技术测序方面的挑战限制了研究。我们使用独特的分子标识符、高深度大规模平行测序和定制分析技术,利用重复样本和正交确认,鉴定了来自6个人类ADPKD肾脏不同区域的24个完整囊肿的体细胞二次命中突变。获得PKD1和PKD2的平均覆盖深度分别为1166个和539个。58%(14/24)的囊肿可检测到PKD1体细胞变异,其中5/6的参与者至少有一个囊肿具有体细胞变异。我们证明在终末期ADPKD人类肾脏的一部分囊肿中可以检测到低频体细胞突变。需要进一步的研究来了解这种体细胞突变的驱动因素。
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引用次数: 0
Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology. 分析外显子缺失在一个大的人口研究提供了新的见解NRXN1病理。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00450-8
Simone Montalbano, Morten Dybdahl Krebs, Anders Rosengren, Morteza Vaez, Kajsa-Lotta Georgii Hellberg, Preben B Mortensen, Anders D Børglum, Daniel H Geschwind, Armin Raznahan, Wesley K Thompson, Dorte Helenius, Thomas Werge, Andrés Ingason

The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions. We used the iPSYCH2015 case-cohort sample to obtain unbiased estimates of the prevalence of NRXN1 deletions and their associated risk of autism, schizophrenia, depression, and ADHD. Most exon-disrupting deletions affected exons specific to the alpha isoform, and almost half of the non-exonic deletions represented a previously reported segregating founder deletion. Carriage of exon-disrupting NRXN1 deletions was associated with a threefold and twofold increased risk of autism and ADHD, respectively, whereas no significantly increased risk of depression or schizophrenia was observed. Our results highlight the importance of using population-based samples in genetic association studies.

NRXN1位点是非复发性拷贝数变异的热点,在病例对照研究中,外显子破坏NRXN1缺失与神经发育障碍的风险增加有关。然而,目前缺乏相应的基于人群的患病率和疾病相关风险估计。此外,大多数研究没有区分影响不同NRXN1剪接变异体外显子的缺失,也没有考虑内含子缺失。我们使用iPSYCH2015病例队列样本来获得NRXN1缺失的患病率及其与自闭症、精神分裂症、抑郁症和ADHD相关的风险的无偏估计。大多数外显子破坏缺失影响了α同工型的外显子,几乎一半的非外显子缺失代表了先前报道的分离性创始人缺失。携带破坏外显子的NRXN1缺失分别与自闭症和ADHD风险增加三倍和两倍相关,而未观察到抑郁症或精神分裂症风险显著增加。我们的结果强调了在遗传关联研究中使用基于群体的样本的重要性。
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引用次数: 0
Implementing genomic newborn screening as an effective public health intervention: sidestepping the hype and criticism. 实施基因组新生儿筛查作为有效的公共卫生干预:回避炒作和批评。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00451-7
Jan M Friedman
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引用次数: 0
Functional assessment of IDUA variants of uncertain significance identified by newborn screening. 新生儿筛查发现的不确定意义的IDUA变异的功能评估。
IF 4.7 2区 医学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-19 DOI: 10.1038/s41525-024-00457-1
Seok-Ho Yu, Francyne Kubaski, Gavin Arno, Whitney Phinney, Tim C Wood, Heather Flanagan-Steet, Laura M Pollard, Richard Steet

With the expansion of newborn screening efforts for MPS disorders, the number of identified variants of uncertain significance in IDUA continues to increase. To better define functional consequences of identified IDUA variants, we developed a HEK293-based expression platform that can be used to determine the relative specific activity of variant α-iduronidases by combining a fluorescence-based activity assay and semi-quantitative western blotting. We employed the current platform to characterize over thirty different IDUA variants, including known benign and pathogenic variants, as well as multiple variants of uncertain significance identified through newborn screening. This analysis allowed the stratification of variant enzymes based on their relative specific activity, and uncovered distinct effects of the different variants on enzyme folding, processing, and stability. While relative specific activity serves as a useful first-level test for enzyme function, our observations reinforce the need for secondary analyses of enzyme function to fully assess variant pathogenicity.

随着新生儿MPS疾病筛查工作的扩大,在IDUA中发现的不确定意义的变异数量继续增加。为了更好地确定已鉴定的IDUA变体的功能后果,我们开发了一个基于hek293的表达平台,该平台可以通过结合荧光活性测定和半定量western blotting来确定变体α-iduronidase的相对特异性活性。我们使用当前的平台来描述超过30种不同的IDUA变异,包括已知的良性和致病变异,以及通过新生儿筛查确定的不确定意义的多种变异。该分析允许基于其相对特定活性对变异酶进行分层,并揭示了不同变异对酶折叠、加工和稳定性的不同影响。虽然相对特异活性可以作为酶功能的一级测试,但我们的观察结果强调了对酶功能进行二次分析以充分评估变异致病性的必要性。
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引用次数: 0
期刊
NPJ Genomic Medicine
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