A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound

Abstract

Objective Conventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide polymorphism‐array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first‐degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. Results We established a genetic rES‐based diagnosis in 8 out of 23 fetuses (35%) without QF‐PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker‐Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8‐20) days. Conclusion Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review

“…Other studies suggest clinical impact or influence on management in 26%-70% [13,14,25], however number of ongoing pregnancies at time of PES and resulting impact is smaller in these studies and the exact definition of clinical impact and management varies.…”

“…Molecular diagnosis in cases of structural malformation allows for greater diagnostic accuracy and can have implications for management of pregnancy; whilst studies are limited in this area, decision making has reportedly been impacted in up to 70% [13][14][15][16].…”

Whole Genome Sequencing in the Evaluation of Fetal Structural Anomalies: A Parallel Test with Chromosomal Microarray Plus Whole Exome Sequencing

“…The additional information provided by WGS allowed precise determination of the risk of recurrence and could guide clinical management. However, the cost and data analysis challenges for applying WGS in prenatal diagnosis should not be ignored, and six fetuses with trisomy 21/18/13 who did not undergo serum screening or noninvasive prenatal screening (NIPS) were identified by WGS in our study, reminding us to perform a reliable, rapid, and cost-effective test, such as quantitative fluorescence polymerase chain reaction (QF-PCR) [ 31 ], to exclude common fetal chromosomal aneuploidies before performing WGS, especially for fetuses that did not undergo serum screening or NIPS, which seemed to be a more reasonable test path in clinical practice.…”

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

“…It may not only provide a prognosis that allows parents to make better informed choices about continuing or terminating the pregnancy, where termination is legally possible in China until 28 weeks of gestation and is possible after this time under exceptional circumstances, but also may help the obstetrician determine the best obstetric management, such as the delivery mode, and help the neonatologists in optimizing neonatal care. Recently, the procedure of simultaneous detection of CNVs and SNVs/indels following normal QF-PCR results has been applied in prenatal diagnosis [19]. In our cohort of study, only 16 cases with ultrasound anomalies were found in the early gestation (≤14 weeks), while 67 fetuses were found in the second trimester and even in the third trimester.…”