European Journal of Human Genetics最新文献

英文中文

Clinical implementation of polygenic risk scores. 多基因风险评分的临床实施。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-29 DOI: 10.1038/s41431-025-01931-9

E Roberts, N Flaum, D G Evans

引用次数: 0

Uncertainty, ethics, and progress in genomic medicine 基因组医学的不确定性、伦理和进展

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-29 DOI: 10.1038/s41431-025-01955-1

Seda Sinem Zonuzi

引用次数: 0

N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder. CACNB1的n端截断变异导致一种新的先天性肌肉疾病。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-29 DOI: 10.1038/s41431-025-01944-4

Asier Iturrate, Nurit Assia Batzir, Ranit Jaron, David Garcia-Valentin, Julian Nevado, Jair Tenorio-Castano, Pablo Lapunzina, Kamila Lee, Rotem Greenberg, Dvora Sassi, Sharon Aharoni, Alla Kuzminsky, Lina Basel-Salmon, Naama Orenstein, Yakov Fellig, Shay Ben-Shachar, Dina Marek-Yagel, Victor L Ruiz-Perez

Excitation-contraction (EC) coupling is an essential process for skeletal muscle function. Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of CACNB1 in the affected individuals from each family. CACNB1 encodes the β1 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca²⁺ channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all CACNB1 transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified CACNB1 variants was further validated by replicating one of them (c.85-1G>A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of β1 subunits, these cells displayed severely reduced protein levels of α1S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in CACNB1 cause a new congenital muscular disorder.

兴奋-收缩耦合是骨骼肌功能的重要过程。不同EC偶联成分的致病变异先前与各种神经肌肉疾病有关。在这项研究中，我们的目的是确定遗传病因的肌肉状况的特点是早发性肌肉无力，CK升高，上睑下垂和低体重，观察到三个个体从两个不相关的近亲家庭。在一个家庭的多个个体中进行的外显子组测序（ES），以及在另一个家庭的先显子中基于SNP阵列的纯合子定位，揭示了每个家庭中受影响个体的CACNB1第二外显子的不同纯合子功能缺失变异。CACNB1编码骨骼肌二氢吡啶受体（DHPR）的β1亚基，DHPR是一个电压门控的Ca2+通道，在EC偶联中起主要作用。鉴定的变异在LHCN-M2人成肌细胞中的分子影响进行了评估。LHCN-M2野生型肌管的长读RNA测序显示，在分化的骨骼肌细胞中，几乎所有的CACNB1转录异构体都含有外显子2，因此会受到该外显子遗传变异的影响。通过crispr - cas9介导的碱基编辑，在LHCN-M2细胞中复制其中一个（c.85-1G>A），进一步验证了所鉴定的CACNB1变异的致病性。对LHCN-M2编辑的肌管的分析表明，除了β1亚基的缺失外，这些细胞的α1S蛋白水平严重降低，α1S是DHPR的成孔亚基。我们得出结论，CACNB1的致病变异引起一种新的先天性肌肉疾病。

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引用次数: 0

The importance of accurate phenotyping in large-scale analyses of common disorders such as hearing loss 准确的表型在听力损失等常见疾病的大规模分析中的重要性。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-27 DOI: 10.1038/s41431-025-01957-z

Morag A. Lewis, Bradley A. Schulte, Judy R. Dubno, Karen P. Steel

Age-related hearing loss (ARHL) is a common, complex disease with high heritability, but its underlying genetic landscape remains unclear. Studying such a condition requires large cohorts, detailed genotyping, and deep phenotyping. However, while large cohorts with next-generation sequence data are becoming increasingly common, the challenge of administering audiometric tests at scale has meant that in-depth auditory phenotyping is rarely included. Here we present our analyses of three cohorts with different forms of phenotype data, which reveal the differences made by even small changes in phenotyping. Detailed audiometry enables interrogation of genetic data by auditory phenotypes, but if these data are not available, self-reports of hearing difficulty may also serve. However, relying on medical records alone is ineffective for classifying biobank participants for a common condition like ARHL, and is likely to result in many people being wrongly classified in the control group.

年龄相关性听力损失（ARHL）是一种常见的复杂疾病，具有高遗传性，但其潜在的遗传景观尚不清楚。研究这种情况需要大量的队列、详细的基因分型和深入的表型分型。然而，虽然具有下一代序列数据的大型队列越来越普遍，但大规模进行听力测试的挑战意味着很少包括深度听觉表型。在这里，我们提出了我们的分析与不同形式的表型数据的三个队列，这揭示了差异，甚至在表型上的微小变化。详细的听力测量可以通过听觉表型来询问基因数据，但如果这些数据不可用，听力困难的自我报告也可以起作用。然而，仅依靠医疗记录对ARHL等常见疾病的生物库参与者进行分类是无效的，并且可能导致许多人被错误地分类为对照组。

引用次数: 0

From screening to strategy: Clinical implications of COL4A3/COL4A4 variants found in reproductive genetic testing. 从筛选到策略：在生殖基因检测中发现COL4A3/COL4A4变异的临床意义

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-27 DOI: 10.1038/s41431-025-01953-3

Gráinne Butler, David J Amor, Catherine Quinlan

Reproductive genetic carrier screening (RGCS) is expanding in both public and private healthcare. The primary aim is to identify carrier status for genetic disorders, inform reproductive decision making and promote reproductive autonomy. As screening panels have increased, the potential for findings with personal health implications rises. We report the prevalence of COL4A3/COL4A4 heterozygous variants within a population undergoing RGCS in a private setting and propose a comprehensive management plan for the ongoing care of this patient cohort. Acknowledging that comprehensive guidelines exist for genetic testing and management of Alport syndrome as a broad patient group, this communication seeks to highlight the increasingly common finding of autosomal dominant Alport syndrome and proposes accessible and practical strategies for the clinicians encountering these patients.

生殖遗传载体筛查（RGCS）在公共和私人医疗保健中都在扩大。主要目的是识别遗传疾病的携带者状态，为生殖决策提供信息，促进生殖自主。随着筛查小组的增加，对个人健康影响的潜在发现也在增加。我们报告了COL4A3/COL4A4杂合变异体在私人环境中接受RGCS的人群中的患病率，并为该患者队列的持续护理提出了综合管理计划。鉴于Alport综合征作为一个广泛的患者群体存在着全面的基因检测和管理指南，本文旨在强调常染色体显性Alport综合征日益普遍的发现，并为遇到这些患者的临床医生提出可获得和实用的策略。

引用次数: 0

PKD1 5’UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development PKD1 5'UTR变异体是ADPKD中一种罕见的病因，提示了治疗发展的新焦点。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-26 DOI: 10.1038/s41431-025-01949-z

Laura Wedd, Yvonne Hort, Chirag Patel, John A. Sayer, Rocio Rius, Andrew J. Mallett, Denny L. Cottle, Ian M. Smyth, Timothy Furlong, John Shine, Amali Mallawaarachchi

Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5′untranslated region (UTR). We then designed a PKD1 5′UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.−69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5′UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5′UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5′-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5′UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.

常染色体显性多囊肾病（ADPKD）由PKD1和PKD2的致病变异引起，是肾衰竭最常见的单基因原因。大约10%的ADPKD患者在编码区集中的基因组检测后仍未被诊断出来。调控区域的非编码变异不是ADPKD的确定病因。我们在未确诊的ADPKD患者的主要队列（n = 20）中进行了调控区分析，然后将该分析扩展到澳大利亚KidGen队列（n = 42）和Genomics England罕见疾病队列（n = 1320）中未确诊的囊性肾病患者。通过基因组分析，我们在PKD1 5'非翻译区（UTR）发现了两种罕见的潜在致病变异。然后，我们设计了PKD1 5' utr -荧光素酶翻译实验来表征这些体外变异，结果表明PKD1变异c - 69dupg与野生型相比，使PKD1主开放阅读框的翻译效率降低了约87% (p

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引用次数: 0

A heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy 包含SPTAN1的9q34杂合缺失是远端肌病的原因。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-25 DOI: 10.1038/s41431-025-01938-2

Liedewei Van de Vondel, Jonathan De Winter, Alice Monticelli, Natacha Camacho, Tine Deconinck, Katrien Janssens, Goedele Malfroid, Alicia Alonso-Jiménez, German Demidov, Steven Laurie, Willem De Ridder, Biljana Ermanoska, Vincent Timmerman, Jonathan Baets

We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The deletion was detected through exome-sequencing based copy number variant (CNV) detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin. SPTAN1 loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role of SPTAN1 haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.

我们报告了一个患有儿童期远端肌无力的家族，其中包含SPTAN1基因的杂合染色体9q34缺失。该缺失是通过基于外显子组测序的拷贝数变异（CNV）检测检测到的，在4名患者中分离，在另外2名亲属中非渗透。肌电图，肌肉MRI和肌肉活检显示肌病表型。使用qPCR和western blotting对患者来源的成纤维细胞研究了缺失的细胞后果，结果显示RNA减少，但蛋白质水平没有减少。肌肉组织免疫细胞化学未发现α- ii -谱素减少。SPTAN1功能丧失变异曾被报道引起远端遗传性运动神经病变和最近的远端肌病。在这里，我们证实SPTAN1单倍体功能不全是远端肌病的一个原因。我们提出了α- ii -谱蛋白的年龄依赖性缺乏，并建议在重定向外显子组测序中检测CNV作为重要的诊断工具。

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引用次数: 0

Pharmacogenomics in drug therapy: global regulatory guidelines for managing high-risk drug reactions 药物治疗中的药物基因组学：管理高风险药物反应的全球监管指南。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-24 DOI: 10.1038/s41431-025-01950-6

Safa Omran, Siew Hua Gan, Siew Li Teoh

Pharmacogenomics is rapidly transforming precision medicine, yet regulatory policies governing its implementation vary widely across countries. This review aims to provide a global perspective on pharmacogenomics guidelines, with a particular focus on high-risk drug reactions such as carbamazepine therapy-induced severe cutaneous adverse reactions. Carbamazepine was selected as a representative example due to its inclusion on the World Health Organization’s essential medicines list and its well-documented association with high-risk alleles, which are linked to severe cutaneous adverse reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis—conditions with significant mortality rates. Two databases, Overton and Dimensions, were searched to identify relevant national guidelines and policy documents in English. Countries were identified based on document availability and access to governmental sources. The review revealed that all examined countries recognized genetic variation in carbamazepine response within their guidelines, showing notable consistency. However, religious implications related to pharmacogenomics were largely absent. The findings also indicated a growing global momentum toward integrating pharmacogenomics into healthcare systems, although the depth and scope of regulation differ. The United States stands out for its comprehensive pharmacogenomics policy framework, which extends to clinical and industry settings. Lessons from the U.S. model can inform policy development in other regions, tailored to each country’s healthcare infrastructure and cultural context. In conclusion, global harmonization of pharmacogenomics policies is essential to foster international collaboration, enable data sharing, and enhance the safe and equitable implementation of pharmacogenomics in clinical practice.

药物基因组学正在迅速改变精准医疗，但各国实施药物基因组学的监管政策差异很大。本综述旨在提供药物基因组学指南的全球视角，特别关注高风险药物反应，如卡马西平治疗引起的严重皮肤不良反应。卡马西平被选为一个代表性的例子，因为它被列入世界卫生组织的基本药物清单，并且有充分证据表明它与高风险等位基因有关，这些等位基因与严重的皮肤不良反应有关，如史蒂文斯-约翰逊综合征和中毒性表皮坏死松解，这些情况具有很高的死亡率。检索了两个数据库，即Overton和Dimensions，以确定相关的英文国家准则和政策文件。根据文件的可得性和获得政府来源的机会确定了国家。审查结果显示，所有被检查的国家都在其指导方针内承认卡马西平反应的遗传变异，显示出显著的一致性。然而，与药物基因组学相关的宗教含义在很大程度上是缺席的。研究结果还表明，将药物基因组学整合到医疗保健系统的全球势头正在增长，尽管监管的深度和范围有所不同。美国因其全面的药物基因组学政策框架而脱颖而出，该框架延伸到临床和工业环境。美国模式的经验教训可以为其他地区的政策制定提供参考，并根据每个国家的医疗基础设施和文化背景进行调整。总之，药物基因组学政策的全球协调对于促进国际合作、实现数据共享以及加强药物基因组学在临床实践中的安全和公平实施至关重要。

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引用次数: 0

LNKing genotype to phenotype: the expanding clinical spectrum of SH2B3 disorders. 连接基因型与表型：扩大SH2B3疾病的临床谱。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-23 DOI: 10.1038/s41431-025-01942-6

Enrico Attardi, Marcin W Wlodarski

引用次数: 0

Expanding the molecular spectrum of aggrecanopathies: exploring 24 patients with ACAN significant variants 扩大聚集性病变的分子谱：探索24例ACAN显著变异患者。

IF 4.6 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

European Journal of Human Genetics

Pub Date : 2025-09-23 DOI: 10.1038/s41431-025-01943-5

Melek Trigui, Nathalie Pallares-Ruiz, David Geneviève, Cyril Amouroux, Thomas Edouard, Sabine Sigaudy, Marjolaine Willems, Mouna Barat-Houari

Short stature is a prevalent clinical manifestation in children. While certain causes of short stature can be readily identifiable through routine biological tests, often physicians struggle to ascertain any underlying pathogenic cause, resulting in the diagnosis of idiopathic short stature (ISS). Aggrecan, encoded by ACAN, plays a crucial role in cartilage function and bone growth. The aim of our study is to establish a genotype-phenotype correlation in 24 patients carrying distinct ACAN variants. We conducted a panel-based analysis, including 82 genes associated with genetic skeletal disorders and/or short stature, in 388 French patients who consulted for short stature and/or or skeletal features. Genotype-phenotype correlation analysis was performed for all included subjects. Of all positive patients, 24 (≃20%) were found to carry pathogenic or likely pathogenic ACAN variants distributed across the gene, 20 of which had not been previously reported. We report 23 heterozygous cases and one original case with a homozygous SNV. Two patients harboured the same novel nonsense variant, yet exhibited different phenotypes. Familial studies performed in 21 families demonstrated that ACAN variants were inherited in 20 cases. The cohort demonstrated marked phenotypic heterogeneity, even among affected members within the same family. Radiological skeletal abnormalities were observed in 66% of patients. A comprehensive genomic approach is crucial to identify the true proportion of ISS with a monogenic condition. Our results expand the number of pathogenic ACAN variants with their associated phenotypic spectrum. Aggrecanopathies are heterogeneous and particularly frequent in apparently ISS, even without overt skeletal dysplasia.

身材矮小是儿童常见的临床表现。虽然矮小的某些原因可以很容易地通过常规的生物学检查确定，但医生往往很难确定任何潜在的致病原因，从而导致特发性矮小（ISS）的诊断。由ACAN编码的聚集蛋白在软骨功能和骨生长中起着至关重要的作用。我们研究的目的是在24例携带不同ACAN变异的患者中建立基因型-表型相关性。我们对388名因身材矮小和/或骨骼特征就诊的法国患者进行了一项基于小组的分析，包括82个与遗传性骨骼疾病和/或身材矮小相关的基因。对所有纳入的受试者进行基因型-表型相关分析。在所有阳性患者中，24个（20%）被发现携带跨基因的致病性或可能致病性ACAN变异，其中20个以前没有报道过。我们报告了23例杂合子病例和1例纯合子SNV原发病例。两名患者携带相同的新型无义变异，但表现出不同的表型。在21个家庭中进行的家族性研究表明，在20例中遗传了ACAN变异。该队列显示出显著的表型异质性，甚至在同一家族的受影响成员中也是如此。66%的患者出现骨骼影像学异常。一个全面的基因组方法是至关重要的，以确定ISS与单基因条件的真实比例。我们的研究结果扩大了致病性ACAN变异及其相关表型谱的数量。聚集性病变是异质性的，在明显的ISS中尤其常见，即使没有明显的骨骼发育不良。

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