Abstract：
To evaluate the utility of trio-based prenatal exome sequencing (pES), incorporating splice-site and mitochondrial genome assessment, in the prenatal diagnosis of fetuses with ultrasound anomalies and normal copy-number variant sequencing (CNV-seq) results.
This was a prospective study of 90 ongoing pregnancies with ultrasound anomalies that underwent trio-based pES after receiving normal CNV-seq results, from September 2020 to November 2021, in a single center in China. By using pES with a panel encompassing exome coding and splicing regions as well as mitochondrial genome for fetuses and parents, we identified the underlying genetic causes of fetal anomalies, incidental fetal findings and parental carrier status. Information on pregnancy outcome and the impact of pES findings on parental decision-making was collected.
Of the 90 pregnancies included, 28 (31.1%) received a diagnostic result that could explain the fetal ultrasound anomalies. The highest diagnostic yield was noted for brain abnormalities (3/6 (50.0%)), followed by hydrops (4/9 (44.4%)) and skeletal abnormalities (13/34 (38.2%)). Collectively, 34 variants of 20 genes were detected in the 28 diagnosed cases, with 55.9% (19/34) occurring de novo. Variants of uncertain significance (VUS) associated with fetal phenotypes were detected in six (6.7%) fetuses. Interestingly, fetal (n = 4) and parental (n = 3) incidental findings (IFs) were detected in seven (7.8%) cases. These included two fetuses carrying a de-novo likely pathogenic (LP) variant of the CIC and FBXO11 genes, respectively, associated with neurodevelopmental disorders, and one fetus with a LP variant in a mitochondrial gene. The remaining fetus presented with unilateral renal dysplasia and was incidentally found to carry a pathogenic PKD1 gene variant resulting in adult-onset polycystic kidney, which was later confirmed to be inherited from the mother. In addition, parental heterozygous variants associated with autosomal recessive diseases were detected in three families, including one with additional fetal diagnostic findings. Diagnostic results or fetal IFs contributed to parental decision-making about termination of the pregnancy in 26 families (26/72 (36.1%)), while negative pES results or identification of VUS encouraged 40 families (40/72 (55.6%)) to continue their pregnancy, which ended in a live birth in all cases.
Trio-based pES can provide additional genetic information for pregnancies with fetal ultrasound anomalies without a CNV-seq diagnosis. The incidental findings and parental carrier status reported by trio-based pES with splice-site and mitochondrial genome analysis extend its clinical application, but careful genetic counseling is warranted. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
This was a prospective study of 90 ongoing pregnancies with ultrasound anomalies that underwent trio-based pES after receiving normal CNV-seq results, from September 2020 to November 2021, in a single center in China. By using pES with a panel encompassing exome coding and splicing regions as well as mitochondrial genome for fetuses and parents, we identified the underlying genetic causes of fetal anomalies, incidental fetal findings and parental carrier status. Information on pregnancy outcome and the impact of pES findings on parental decision-making was collected.
Of the 90 pregnancies included, 28 (31.1%) received a diagnostic result that could explain the fetal ultrasound anomalies. The highest diagnostic yield was noted for brain abnormalities (3/6 (50.0%)), followed by hydrops (4/9 (44.4%)) and skeletal abnormalities (13/34 (38.2%)). Collectively, 34 variants of 20 genes were detected in the 28 diagnosed cases, with 55.9% (19/34) occurring de novo. Variants of uncertain significance (VUS) associated with fetal phenotypes were detected in six (6.7%) fetuses. Interestingly, fetal (n = 4) and parental (n = 3) incidental findings (IFs) were detected in seven (7.8%) cases. These included two fetuses carrying a de-novo likely pathogenic (LP) variant of the CIC and FBXO11 genes, respectively, associated with neurodevelopmental disorders, and one fetus with a LP variant in a mitochondrial gene. The remaining fetus presented with unilateral renal dysplasia and was incidentally found to carry a pathogenic PKD1 gene variant resulting in adult-onset polycystic kidney, which was later confirmed to be inherited from the mother. In addition, parental heterozygous variants associated with autosomal recessive diseases were detected in three families, including one with additional fetal diagnostic findings. Diagnostic results or fetal IFs contributed to parental decision-making about termination of the pregnancy in 26 families (26/72 (36.1%)), while negative pES results or identification of VUS encouraged 40 families (40/72 (55.6%)) to continue their pregnancy, which ended in a live birth in all cases.
Trio-based pES can provide additional genetic information for pregnancies with fetal ultrasound anomalies without a CNV-seq diagnosis. The incidental findings and parental carrier status reported by trio-based pES with splice-site and mitochondrial genome analysis extend its clinical application, but careful genetic counseling is warranted. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
摘要：
为了评估基于三重奏的产前外显子组测序（pES）的实用性，整合剪接位点和线粒体基因组评估，在产前诊断胎儿超声异常和正常拷贝数变异测序（CNV-seq）结果中。
这是一项前瞻性研究，对90例接受正常CNV-seq结果后接受三重奏pES的超声异常进行了前瞻性研究，从2020年9月到2021年11月，在中国的单一中心。通过使用pES和一组包含外显子组编码和剪接区以及胎儿和父母的线粒体基因组，我们确定了胎儿畸形的潜在遗传原因，偶然的胎儿发现和父母携带者状态。收集有关妊娠结局的信息以及pES结果对父母决策的影响。
包括90次怀孕,28人（31.1％）获得了可以解释胎儿超声异常的诊断结果。大脑异常的诊断率最高（3/6（50.0％）），其次是水肿(4/9(44.4%))和骨骼异常(13/34(38.2%))。总的来说，在28例确诊病例中检测到20个基因的34个变异，55.9%(19/34)从头发生。在六个（6.7％）胎儿中检测到与胎儿表型相关的不确定显著性变异（VUS）。有趣的是,在7例(7.8%)中检测到胎儿(n=4)和父母(n=3)的偶然发现(IFs).其中包括两个胎儿携带CIC和FBXO11基因的从头可能致病（LP）变体，分别,与神经发育障碍有关，和一个线粒体基因有LP变异的胎儿。其余胎儿表现为单侧肾发育不良，偶然发现携带致病性PKD1基因变异，导致成年多囊肾，后来被证实是从母亲那里继承的。此外,在三个家庭中检测到与常染色体隐性遗传疾病相关的亲本杂合变体，包括一个额外的胎儿诊断结果。诊断结果或胎儿IFs有助于26个家庭的父母决定终止妊娠（26/72（36.1％）），虽然pES阴性结果或VUS的鉴定鼓励40个家庭(40/72(55.6%))继续怀孕，在所有情况下都以活产告终。
基于Trio的pES可以为没有CNV-seq诊断的胎儿超声异常妊娠提供额外的遗传信息。通过剪接位点和线粒体基因组分析，基于三重奏的pES报告的偶然发现和亲本携带者状态扩展了其临床应用，但谨慎的遗传咨询是有必要的.©2022国际妇产科超声学会。
这是一项前瞻性研究，对90例接受正常CNV-seq结果后接受三重奏pES的超声异常进行了前瞻性研究，从2020年9月到2021年11月，在中国的单一中心。通过使用pES和一组包含外显子组编码和剪接区以及胎儿和父母的线粒体基因组，我们确定了胎儿畸形的潜在遗传原因，偶然的胎儿发现和父母携带者状态。收集有关妊娠结局的信息以及pES结果对父母决策的影响。
包括90次怀孕,28人（31.1％）获得了可以解释胎儿超声异常的诊断结果。大脑异常的诊断率最高（3/6（50.0％）），其次是水肿(4/9(44.4%))和骨骼异常(13/34(38.2%))。总的来说，在28例确诊病例中检测到20个基因的34个变异，55.9%(19/34)从头发生。在六个（6.7％）胎儿中检测到与胎儿表型相关的不确定显著性变异（VUS）。有趣的是,在7例(7.8%)中检测到胎儿(n=4)和父母(n=3)的偶然发现(IFs).其中包括两个胎儿携带CIC和FBXO11基因的从头可能致病（LP）变体，分别,与神经发育障碍有关，和一个线粒体基因有LP变异的胎儿。其余胎儿表现为单侧肾发育不良，偶然发现携带致病性PKD1基因变异，导致成年多囊肾，后来被证实是从母亲那里继承的。此外,在三个家庭中检测到与常染色体隐性遗传疾病相关的亲本杂合变体，包括一个额外的胎儿诊断结果。诊断结果或胎儿IFs有助于26个家庭的父母决定终止妊娠（26/72（36.1％）），虽然pES阴性结果或VUS的鉴定鼓励40个家庭(40/72(55.6%))继续怀孕，在所有情况下都以活产告终。
基于Trio的pES可以为没有CNV-seq诊断的胎儿超声异常妊娠提供额外的遗传信息。通过剪接位点和线粒体基因组分析，基于三重奏的pES报告的偶然发现和亲本携带者状态扩展了其临床应用，但谨慎的遗传咨询是有必要的.©2022国际妇产科超声学会。
