Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation

Abstract

Congenital malformations diagnosed by ultrasound screening complicate 3–5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of prenatally diagnosed fetal malformations are associated with aneuploidy or copy number variants, detected by conventional karyotyping, QF-PCR and microarray techniques, however monogenic disorders are not diagnosed by these tests. Next generation sequencing as a secondary prenatal genetic test offers additional diagnostic yield for congenital abnormalities deemed to be potentially associated with an underlying genetic aetiology, as demonstrated by two large cohorts: the ‘Prenatal assessment of genomes and exomes’ (PAGE) study and ‘Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study’ performed at Columbia University in the US. These were large and prospective studies but relatively ‘unselected’ congenital malformations, with little Clinical Genetics input to the pre-test selection process. This review focuses on the incremental yield of next generation sequencing in single system congenital malformations, using evidence from the PAGE, Columbia and subsequent cohorts, with particularly high yields in those fetuses with cardiac and neurological anomalies, large nuchal translucency and non-immune fetal hydrops (of unknown aetiology). The total additional yield gained by exome sequencing in congenital heart disease was 12.7%, for neurological malformations 13.8%, 13.1% in increased nuchal translucency and 29% in non-immune fetal hydrops. This demonstrates significant incremental yield with exome sequencing in single-system anomalies and supports next generation sequencing as a secondary genetic test in routine clinical care of fetuses with congenital abnormalities.

The crucial role of titin in fetal development: recurrent miscarriages and bone, heart, and muscle anomalies characterize the severe end of titinopathies spectrum

“…36 In line with those reflections, although attention must be paid to offering proper genetic counseling, we believe that a prompt diagnosis can be of great benefit to the family, allowing the parents to face the future and avoid repeated negative pregnancy experiences that could have major psychological and physical repercussions. 37,38 We are aware that our research may have some limitations. First of all, prenatal ultrasound examination is operator-dependent, and thus the prevalence of antenatal signs may be influenced by reporting bias.…”

“…36 In line with those reflections, although attention must be paid to offering proper genetic counseling, we believe that a prompt diagnosis can be of great benefit to the family, allowing the parents to face the future and avoid repeated negative pregnancy experiences that could have major psychological and physical repercussions. 37,38…”

Prenatal Detection of a FOXF1 Deletion in a Fetus with ACDMPV and Hydronephrosis

“…While the most commonly applied approaches for prenatal screening are karyotype or microarray tests, GS is now increasingly being utilized [ 35 ]. The use of next-generation sequencing (NGS) as a tool in prenatal testing allows for rapid and effective detection of various molecular defects, including both CNVs and SNVs [ 36 ].…”

Prenatal whole‐exome sequencing in fetuses with increased nuchal translucency

“…WES can greatly increase the diagnostic yield in fetuses with structural abnormalities and those initially presenting with non‐isolated increased NT (Chen et al, 2020; Drury et al, 2015; Emms et al, 2022; Lord et al, 2019; Petrovski et al, 2019; Sparks et al, 2020; Yang et al, 2020). Thus, in this study, we excluded initially non‐isolated cases, and only focused on those initially isolated, which could greatly reduce the detection rate in this study.…”