Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1.

IF 5.5 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Anthony R Anzell, Carter White, Brenda Diergaarde, Jenna C Carlson, Beth L Roman
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引用次数: 0

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is a near-fully penetrant autosomal dominant disorder characterized by nosebleeds, anemia, and arteriovenous malformations. The great majority of HHT cases are caused by heterozygous loss-of-function mutations in ACVRL1 or ENG, which encode proteins that function in bone morphogenetic protein signaling. HHT prevalence is estimated at 1 in 5000 and is accordingly classified as rare. However, HHT is suspected to be underdiagnosed.

Methods: To estimate the true prevalence of HHT, we summed allele frequencies of predicted pathogenic variants in ACVRL1 and ENG using 3 methods. For method 1, we included Genome Aggregation Database (gnomAD v4.1) variants with ClinVar annotations of pathogenic or likely pathogenic, plus unannotated variants with a high probability of causing disease. For method 2, we evaluated all ACVRL1 and ENG gnomAD variants using threshold filters based on accessible in silico pathogenicity prediction algorithms. For method 3, we developed a machine learning-based classification system to improve the classification of missense variants.

Results: We calculated an HHT prevalence of between 2.1 in 5000 and 11.9 in 5000, or 2 to 12× higher than current estimates. Application of our machine learning-based classification method revealed missense variants as the greatest contributor to pathogenic allele frequency and similar HHT prevalence across genetic ancestries.

Conclusions: Our results support the notion that HHT is underdiagnosed and that HHT prevalence may be above the threshold of a rare disease.

从GnomAD等位基因频率计算出遗传性出血性毛细血管扩张症在ENG和ACVRL1中预测的致病变异。
背景:遗传性出血性毛细血管扩张症(HHT)是一种几乎完全渗透的常染色体显性遗传病,以流鼻血、贫血和动静脉畸形为特征。绝大多数HHT病例是由ACVRL1或ENG的杂合功能缺失突变引起的,它们编码在骨形态发生蛋白信号传导中起作用的蛋白质。HHT患病率估计为1 / 5000,因此被列为罕见。然而,HHT被怀疑未被充分诊断。方法:为了估计HHT的真实患病率,我们使用3种方法对ACVRL1和ENG预测致病变异的等位基因频率进行了汇总。对于方法1,我们纳入了基因组聚集数据库(gnomAD v4.1)中具有ClinVar致病或可能致病注释的变体,以及具有高致病概率的未注释变体。对于方法2,我们使用基于可访问的计算机致病性预测算法的阈值过滤器评估所有ACVRL1和ENG gnomAD变体。对于方法3,我们开发了一个基于机器学习的分类系统来改进错义变体的分类。结果:我们计算出HHT患病率在5000人中2.1到11.9之间,比目前的估计高2到12倍。我们基于机器学习的分类方法的应用表明,错义变异是致病等位基因频率和遗传祖先中相似的HHT患病率的最大贡献者。结论:我们的研究结果支持HHT未被充分诊断的观点,HHT患病率可能高于罕见病的阈值。
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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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