Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance

整合 KCNH2 变体特异性特征和杂合子表型来估计长 QT 外显率

基本信息

  • 批准号:
    10557122
  • 负责人:
  • 金额:
    $ 59.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Sequencing an individual’s genome now costs less than many routine medical procedures. A resulting vision is that everyone will have their genome sequenced early in life to enable individualized medical advice about disease prevention and drug selection. A major concern with this vision, however, is proper interpretation of the overwhelming volume of discovered novel and rare variants. In other contexts, a new diagnostic test can be benchmarked and validated in studies that compare large populations with and without a disorder to determine the predictive value of a positive result. In the genetic sequencing context, however, a positive test for most variants cannot be applied to enough heterozygous individuals for a definitive association with disease. Pathogenic variants in KCNH2 (a.k.a. hERG, a cardiac potassium channel gene critical for cardiomyocyte repolarization) can cause sudden cardiac death in the young and can predispose carriers to drug-induced arrhythmias. Genetic variants in KCNH2 are responsible for ~ 6% of autopsy-negative sudden unexplained death in the young and ~ 1% of sudden infant death syndrome cases. Additionally, among heterozygous carriers of variants in KCNH2, women are at greater overall risk of a severe event (including sudden cardiac death) which is increased in the postpartum period. Since most disease-associated variants in KCNH2 are rare, full exome sequencing has the potential to identify those individuals at greater risk early in life before any phenotype manifests. However, even among heterozygous carriers of KCNH2 variants definitively associated with disease, not all develop the same phenotype. To address the challenge of variant interpretation, the American College of Medical Genetics and Genomics suggests criteria to incorporate variant population, functional, computational, and segregation data using several described heuristics. Our foundational hypothesis is that clinically meaningful knowledge is lost in the compression of these variant-specific data to a dichotomous classification. To investigate this hypothesis, we will generate in vitro data for all missense variants in KCNH2 prospectively, build a prediction model of disease penetrance, and validate resulting predictions against the incidence of arrhythmias and cardiac events for variants observed in the Electronic Medical Records and Genomics Network (eMERGE), a Leducq Transatlantic Network, and the UK Biobank.
项目总结/文摘

项目成果

期刊论文数量(0)
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Brett M Kroncke其他文献

Brett M Kroncke的其他文献

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{{ truncateString('Brett M Kroncke', 18)}}的其他基金

Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance
整合 KCNH2 变体特异性特征和杂合子表型来估计长 QT 外显率
  • 批准号:
    10343134
  • 财政年份:
    2022
  • 资助金额:
    $ 59.67万
  • 项目类别:
SCN5A (Nav1.5): Predicting the Consequence of Missense Single- Nucleotide Polymorphisms.
SCN5A (Nav1.5):预测错义单核苷酸多态性的后果。
  • 批准号:
    9224146
  • 财政年份:
    2017
  • 资助金额:
    $ 59.67万
  • 项目类别:
Structural rationale for open-state-inducing mutation in human Iks-producing potassium channel complex
产生人 Iks 的钾通道复合物中开放态诱导突变的结构原理
  • 批准号:
    8834238
  • 财政年份:
    2015
  • 资助金额:
    $ 59.67万
  • 项目类别:

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