测量遗传性视网膜疾病的历史变异重分类及其对临床基因检测的影响。

IF 1 4区 医学 Q4 GENETICS & HEREDITY
Karly Kern, Adam Gordon, Andy Drackley, Jennifer Rossen, Valerie Allegretti, Sharon Aufox, Alexander Ing
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引用次数: 0

摘要

遗传性视网膜疾病(IRDs)是临床上和遗传上多样化的疾病,其异质性使得分子诊断具有挑战性。这些挑战可能导致解释不一致,这对IRD的基因靶向治疗有特别的影响。方法:在临床试验队列和ClinVar中评估不一致性。根据美国医学遗传学与基因组学学会(ACMG)和分子病理学协会(AMP)变异解释指南,在一组患有IRD的儿科患者中通过基因检测鉴定出的140个序列变异被重新分类。对2019年12月2日和2022年1月3日的ClinVar数据集进行RPE65基因的不一致分析。结果:儿童队列的不一致率为22.2%。ClinVar的不一致性从23.6%上升到36.6%。讨论:儿童队列中的不一致可能受到ACMG/AMP指南的主观应用和IRD的异质性的影响。指南的主观性、实验室差异和缺乏解释性审查可能是导致ClinVar不一致的原因。改善IRD解释的工作应包括更好地理解IRD的遗传影响和优化该领域的ACMG/AMP指南。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Measuring historical variant reclassification in inherited retinal disease and its impact on clinical genetic testing.

Introduction: Inherited retinal diseases (IRDs) are clinically and genetically diverse conditions whose heterogeneity makes molecular diagnosis challenging. These challenges can lead to interpretation discordance which has a particular impact on gene-targeted therapies for IRD.

Methods: Discordance was evaluated in a clinical testing cohort and in ClinVar. 140 sequence variants identified through genetic testing in a cohort of pediatric participations with IRD were reclassified using the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for variant interpretation. ClinVar datasets from December 2, 2019 and January 3, 2022 for the gene RPE65 were analyzed for discordance.

Results: The discordance rate in the pediatric cohort was 22.2%. Discordance in ClinVar increased from 23.6% to 36.6%.

Discussion: Discordance in the pediatric cohort may have been impacted by subjective application of the ACMG/AMP guidelines and heterogeneity in IRD. Subjectivity in the guidelines, laboratory differences, and lack of interpretation review may have contributed to discordance in ClinVar. Work to improve interpretation for IRD should include better understanding of the genetic influences of IRD and optimization of the ACMG/AMP guidelines for this field.

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来源期刊
Ophthalmic Genetics
Ophthalmic Genetics 医学-眼科学
CiteScore
2.40
自引率
8.30%
发文量
126
审稿时长
>12 weeks
期刊介绍: Ophthalmic Genetics accepts original papers, review articles and short communications on the clinical and molecular genetic aspects of ocular diseases.
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