Interpreting the actionable clinical role of rare variants associated with short QT syndrome.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI:10.1007/s00439-024-02713-x
Estefanía Martínez-Barrios, Andrea Greco, José Cruzalegui, Sergi Cesar, Nuria Díez-Escuté, Patricia Cerralbo, Fredy Chipa, Irene Zschaeck, Leonel Slanovic, Alipio Mangas, Rocío Toro, Josep Brugada, Georgia Sarquella-Brugada, Oscar Campuzano
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Abstract

Genetic testing is recommended in the diagnosis of short QT syndrome. This rare inherited lethal entity is characterized by structural normal hearts with short QT intervals in the electrocardiogram. Few families diagnosed with this arrhythmogenic disease have been reported worldwide so far, impeding a comprehensive understanding of this syndrome. Unraveling the origin of the disease helps to the early identification of genetic carriers at risk. However, only rare variants with a definite deleterious role should be actionable in clinical practice. Our aim was to perform a comprehensive update and reinterpretation, according to the American College of Medical Genetics and Genomics recommendations of all rare variants currently associated with short QT syndrome. We identified 34 rare variants. Reanalysis showed that only nine variants played a deleterious role associated with a definite short QT syndrome phenotype. These variants were located in the four main genes: KCNQ1, KCNH2, KCNJ2 or SLC4A3. Additional rare variants located in other genes were associated with other conditions with phenotypic shortened QT intervals, but not definite diagnosis of short QT syndrome. Periodically updating of rare variants, especially those previously classified as unknown, helps to clarify the role of rare variants and translate genetic data into clinical practice.

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解读与短 QT 综合征相关的罕见变异的可操作临床作用。
建议在诊断短 QT 综合征时进行基因检测。这种罕见的遗传致死性疾病的特点是心脏结构正常,但心电图上的 QT 间期很短。迄今为止,全世界只有极少数家族确诊患有这种心律失常性疾病,这阻碍了人们对该综合征的全面了解。揭示这种疾病的起源有助于及早发现高危基因携带者。然而,只有具有明确有害作用的罕见变异才能在临床实践中发挥作用。我们的目的是根据美国医学遗传学和基因组学学院的建议,对目前与短 QT 综合征相关的所有罕见变异进行全面更新和重新解释。我们发现了 34 个罕见变异。重新分析表明,只有 9 个变异与明确的短 QT 综合征表型有关。这些变异位于四个主要基因中:KCNQ1、KCNH2、KCNJ2 或 SLC4A3。位于其他基因的其他罕见变异与表型 QT 间期缩短的其他病症有关,但不能确诊为短 QT 综合征。定期更新罕见变异,尤其是那些以前被归类为未知的变异,有助于明确罕见变异的作用,并将基因数据转化为临床实践。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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