Genetics and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Genetics and Precision Medicine Centre, First People's Hospital of Kunming, Kunming, China.
Am J Obstet Gynecol. 2023 Aug;229(2):170.e1-170.e8. doi: 10.1016/j.ajog.2023.01.022. Epub 2023 Jan 27.
Next-generation sequencing for copy number variants is often used as a follow-up investigation of unusual fetal ultrasound results and is capable of detecting copy number variations with a resolution of ∼0.1 Mb. In a prenatal setting, observation and subsequent management of pregnancies with a fetal variant of uncertain significance remains problematic for counseling.
This study aimed to follow the decision-making processes in pregnancies with a fetal variant of uncertain significance and prospectively assess copy number variation interpretations and implications under the newer 2020 American College of Medical Genetics and Genomics guidelines.
In a single prenatal unit, prospective chromosome testing using copy number variation sequencing for 8030 fetuses with unexpected noninvasive findings identified 139 pregnancies with a copy number variation classified as a variant of uncertain significance according to the 2015 American College of Medical Genetics and Genomics guidelines current at the time. Parent-of-origin testing was subsequently performed to determine if the copy number variation was inherited or de novo. All couples were offered specialized genetic counseling to assist in pregnancy management decisions. For the continued pregnancies that reached term, newborns were clinically assessed for evidence of any disease at 0 to 10 months and/or at 2 to 4 years of age.
Of the 139 variants of uncertain significance found, most (78%) were inherited with no evidence of disease in the carrier parent. On the basis of primary ultrasound findings combined with results from noninvasive prenatal screening tests, most inherited variant of uncertain significance pregnancies were continued, whereas most pregnancies involving de novo variants of uncertain significance were terminated. From clinical follow-up of the 113 live births, only 5 showed any evidence of a phenotype that was not apparently related to the original variant of uncertain significance. Prospective reanalysis of the 139 variants of uncertain significance using recent 2020 American College of Medical Genetics and Genomics guidelines changed the status of 24 variants of uncertain significance, with 15 reclassified as benign and 9 as pathogenic. However, the 5 children born with an inherited variant of uncertain significance reclassified as pathogenic showed no evidence of a disease phenotype on clinical follow-up.
The severity of fetal ultrasound findings combined with results from parent-of-origin testing were the key drivers in pregnancy management decisions for patients. According to birth outcomes from continued pregnancies, most variants of uncertain significance proved to be apparently benign in nature and potentially of low risk of adverse disease outcome. There was a discordance rate of 17% for variant of uncertain significance scoring between the 2015 and 2020 American College of Medical Genetics and Genomics guidelines for defining a variant of uncertain significance, suggesting that difficulties remain for predicting true pathogenicity. Nonetheless, with increasing knowledge of population copy number variation polymorphisms, and a more complete assessment for alternative genetic causes, patients having prenatal assessments should feel less anxious when a fetal variant of uncertain significance is identified.
下一代测序技术常用于检测异常胎儿超声结果，并能够以约 0.1 Mb 的分辨率检测拷贝数变异。在产前环境中，对于具有不确定意义的胎儿变异的观察和随后的妊娠管理仍然是咨询的难题。
本研究旨在跟踪具有不确定意义的胎儿变异妊娠的决策过程，并根据较新的 2020 年美国医学遗传学与基因组学学院指南，前瞻性评估拷贝数变异解释及其影响。
在一个单一的产前单位，对 8030 例具有意外非侵入性发现的胎儿进行基于拷贝数变异测序的前瞻性染色体检测，发现 139 例拷贝数变异被归类为不确定意义的变异，根据当时的 2015 年美国医学遗传学与基因组学学院指南。随后进行亲本来源检测以确定拷贝数变异是遗传的还是新发的。所有夫妇都接受了专门的遗传咨询，以帮助做出妊娠管理决策。对于继续妊娠并达到足月的孕妇，对新生儿在 0 至 10 个月和/或 2 至 4 岁时进行临床评估，以寻找任何疾病的证据。
在发现的 139 个不确定意义的变异中，大多数（78%）是遗传的，携带者父母没有疾病证据。基于主要超声发现以及非侵入性产前筛查试验的结果，大多数具有不确定意义的遗传妊娠被继续，而大多数涉及新发不确定意义的变异妊娠被终止。从 113 例活产儿的临床随访中，只有 5 例出现了与原始不确定意义的变异无关的明显表型证据。使用最近的 2020 年美国医学遗传学与基因组学学院指南对 139 个不确定意义的变异进行前瞻性重新分析，改变了 24 个不确定意义的变异的状态，其中 15 个重新分类为良性，9 个为致病性。然而，在重新分类为致病性的 5 例具有遗传不确定意义的变异的儿童中，在临床随访中没有发现疾病表型的证据。
胎儿超声发现的严重程度结合亲本来源检测的结果是患者妊娠管理决策的关键驱动因素。根据继续妊娠的分娩结局，大多数不确定意义的变异本质上似乎是良性的，潜在的不良疾病结局风险较低。在 2015 年和 2020 年美国医学遗传学与基因组学学院指南中，用于定义不确定意义的变异的不确定意义变异评分之间存在 17%的差异率，这表明预测真正的致病性仍然存在困难。尽管如此，随着对人群拷贝数变异多态性认识的不断增加，以及对替代遗传原因的更全面评估，当发现胎儿不确定意义的变异时，进行产前评估的患者应该会感到不那么焦虑。
