靶向外显子测序确定了脑血管疾病队列中的新变异。

IF 3.2 3区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Clinica Chimica Acta Pub Date : 2025-02-01 DOI:10.1016/j.cca.2024.120120
Paul J. Dunn , Neven Maksemous , Robert A. Smith , Heidi G. Sutherland , Larisa M. Haupt , Lyn R. Griffiths
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引用次数: 0

摘要

背景和目的:脑小血管疾病(CSVDs)是一组影响大脑小血管的疾病,可导致严重的神经系统病变,如中风和血管性痴呆。最常见的单基因CSVD是大脑常染色体显性动脉病变伴皮层下梗死和白质脑病(CADASIL),由NOTCH3突变引起。然而,在进行基因检测的CADASIL病例中,只有15-20%存在NOTCH3致病性突变。我们假设CSVD的其他单基因原因可能导致cadasil样CSVD表型。方法:为了验证这一点,我们对50名疑似患有CADASIL但未表现出NOTCH3致病突变的个体进行了全外显子组测序,并对所有单基因形式的CSVD进行了靶向分析。结果:该分析确定了三个影响胶原型IV基因的突变,这些突变可能是CSVD的病因。结论:这表明,当临床怀疑有一种单基因形式的CSVD时,对所有单基因形式的CSVD进行筛查可以提高临床怀疑的单基因CSVD的诊断。然而,尽管有这些发现,大多数NOTCH3阴性的CSVD病例在已知的CSVD基因中没有候选突变,这表明导致该疾病的其他遗传因素尚未确定。
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Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort

Background and aims

Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15–20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3. We hypothesise that other monogenic causes of CSVD may be causing a CADASIL-like CSVD phenotype.

Methods

To test this, we performed whole exome sequencing for 50 individuals suspected of having CADASIL, but did not exhibit a disease-causing mutation in NOTCH3, and applied targeted analysis of all monogenic forms of CSVD.

Results

This analysis identified three mutations affecting the Collagen type IV genes in three individuals likely to be causative of CSVD.

Conclusions

This suggests that screening for all monogenic forms of CSVD when one monogenic form is clinically suspected may improve diagnosis in clinically suspected monogenic CSVD. However, despite these findings, the majority of NOTCH3 negative CSVD cases did not have candidate mutations in known CSVD genes, suggesting that additional genetic factors contributing to the disease are yet to be identified.
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来源期刊
Clinica Chimica Acta
Clinica Chimica Acta 医学-医学实验技术
CiteScore
10.10
自引率
2.00%
发文量
1268
审稿时长
23 days
期刊介绍: The Official Journal of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Clinica Chimica Acta is a high-quality journal which publishes original Research Communications in the field of clinical chemistry and laboratory medicine, defined as the diagnostic application of chemistry, biochemistry, immunochemistry, biochemical aspects of hematology, toxicology, and molecular biology to the study of human disease in body fluids and cells. The objective of the journal is to publish novel information leading to a better understanding of biological mechanisms of human diseases, their prevention, diagnosis, and patient management. Reports of an applied clinical character are also welcome. Papers concerned with normal metabolic processes or with constituents of normal cells or body fluids, such as reports of experimental or clinical studies in animals, are only considered when they are clearly and directly relevant to human disease. Evaluation of commercial products have a low priority for publication, unless they are novel or represent a technological breakthrough. Studies dealing with effects of drugs and natural products and studies dealing with the redox status in various diseases are not within the journal''s scope. Development and evaluation of novel analytical methodologies where applicable to diagnostic clinical chemistry and laboratory medicine, including point-of-care testing, and topics on laboratory management and informatics will also be considered. Studies focused on emerging diagnostic technologies and (big) data analysis procedures including digitalization, mobile Health, and artificial Intelligence applied to Laboratory Medicine are also of interest.
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