Hanna Eileen Marie, Mehawej Cybel, Hoblos Yazid, Rahy Kelven, Megarbane Andre, Chouery Eliane
Department of Computer Science and Mathematics, Lebanese American University, Byblos, Lebanon.
Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
PLoS One. 2025 Jul 18;20(7):e0327471. doi: 10.1371/journal.pone.0327471. eCollection 2025.
Advances in next-generation sequencing enabled its integration into genetic diagnosis and have led to the uncovering of secondary findings. In this paper, we analyzed 500 Lebanese participants for pathogenic and likely-pathogenic variants in 81 recommended genes listed by the American College of Medical Genetics (ACMG). In this retrospective study, 500 individuals seeking genetic diagnosis through Exome Sequencing were included. Variants were analyzed and their pathogenicity assessed based on ACMG/AMP criteria and ClinVar. Secondary findings were identified in 16.8% of cases based on ACMG/AMP criteria, which decreased to 6% when relying on ClinVar. Dominant cardiovascular disease variants were predominant, constituting 6.6% based on ACMG/AMP assessments and 2% according to ClinVar. Additionally, using ACMG/AMP criteria, dominant oncogenic variants were identified in 4.2% of individuals, while recessive pathogenic variants were found in 4.8%. In contrast, ClinVar-based analysis reported these variants in 1% and 2.6% of the cohort, respectively. The high discordance between ACMG/AMP and ClinVar classifications (16.8% vs. 6%) underscores ethical dilemmas in deciding which criteria to prioritize for patient disclosure. Indeed, the absence of ACMG-classified pathogenic or likely pathogenic variants in ClinVar complicates reporting due to a lack of evidence linking them to disease in other individuals. Finally, the significant discrepancy between ACMG/AMP and ClinVar classifications emphasizes the urgent need to harmonize variant databases and update ClinVar entries, particularly for understudied populations such as the Lebanese cohort.
下一代测序技术的进步使其能够融入基因诊断，并导致了次要发现的揭示。在本文中，我们分析了500名黎巴嫩参与者，以寻找美国医学遗传学学院（ACMG）列出的81个推荐基因中的致病和可能致病变异。在这项回顾性研究中，纳入了500名通过外显子组测序寻求基因诊断的个体。根据ACMG/AMP标准和ClinVar对变异进行分析并评估其致病性。根据ACMG/AMP标准，在16.8%的病例中发现了次要发现，而依靠ClinVar时这一比例降至6%。显性心血管疾病变异占主导，根据ACMG/AMP评估为6.6%，根据ClinVar为2%。此外，使用ACMG/AMP标准，在4.2%的个体中发现了显性致癌变异，在4.8%的个体中发现了隐性致病变异。相比之下，基于ClinVar的分析在该队列中分别报告这些变异的比例为1%和2.6%。ACMG/AMP与ClinVar分类之间的高度不一致（16.8%对6%）凸显了在决定优先向患者披露哪些标准时的伦理困境。确实，ClinVar中缺乏ACMG分类的致病或可能致病变异，由于缺乏将它们与其他个体疾病联系起来的证据，使得报告变得复杂。最后，ACMG/AMP与ClinVar分类之间的显著差异强调了迫切需要统一变异数据库并更新ClinVar条目，特别是对于像黎巴嫩队列这样研究不足的人群。
