Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES)

Abstract

BackgroundWhole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound.MethodThirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus.ResultsPathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features.ConclusionWES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0409-z) contains supplementary material, which is available to authorized users.

Prenatally detected copy number variants in a national cohort: A postnatal follow‐up study

“…Over the last 5 years, CMA has increasingly replaced conventional karyotyping for the analysis of invasively obtained samples. The Noninvasive Prenatal Test (NIPT) has a very high uptake in both average and low risk pregnancies, and whole exome sequencing is slowly being introduced in the prenatal setting for certain ultrasonographic anomalies 39 . While invasive prenatal testing suffered a steep decline with the introduction of NIPT, the expansion of NIPT to karyotype resolution has partially reversed this trend, as NIPT‐positive cases need to obtain a confirmatory invasive test.…”

Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis

“…Owing to the breakthrough of molecular technologies such as next-generation sequencing and its reduction of costs over the years, whole-exome sequencing (or exome sequencing, WES) has been applied for both research purposes and clinical use (Drury et al, 2015;Fu et al, 2018;Leung et al, 2018;Normand et al, 2018;Lord et al, 2019;Petrovski et al, 2019). Emerging studies show WES has the ability to provide genetic diagnoses ranging from 9.1% to 32% for the fetuses with a structural anomaly (Drury et al, 2015;Fu et al, 2018;Leung et al, 2018;Normand et al, 2018;Lord et al, 2019;Petrovski et al, 2019), while among these cases, WES yielded diagnoses in 3.2% to 21% of the fetuses with increased NT with/without structural malformations (Drury et al, 2015;Lord et al, 2019;Petrovski et al, 2019). However, most of these studies were conducted on prenatal cohorts after the exclusion of abnormal karyotypes and/or CMA results attributed to the cost and the limited ability of WES in CNV detection (Belkadi et al, 2015).…”

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

“…Adding rapid ES (rES) to the standard diagnostic procedures can reveal an additional 6% to 80% of causes, with a higher yield in fetuses with multiple congenital anomalies or clinical suspicion of a syndrome. 3,4 However, although ES may improve diagnostic yield, implementing prenatal ES is challenging due to uncertainties about the fetal phenotype, ethical counseling issues, the difficulty of variant interpretation, the need to make choices about reporting variants of unknown clinical significance, and the need for short turnaround times. 3,5,6 In this prospective study, we offered rES as a diagnostic test in standard prenatal care in addition to quantitative fluorescentpolymerase chain reaction (QF-PCR) and single nucleotide polymorphism-array (SNP-array) during pregnancy.…”