Whole‐genome sequencing in prenatally detected congenital malformations: prospective cohort study in clinical setting

Abstract

OBJECTIVESTo investigate the diagnostic yield of whole genome sequencing (WGS) in fetuses with various types of congenital malformations referred to a tertiary center for prenatal diagnosis.METHODSIn this prospective study, 50 fetuses with different congenital malformations, negative for trisomies and causative copy number variants, were further analyzed with fetal‐parental trio WGS analysis. Parents were eligible for inclusion if they accepted further investigation following the detection of isolated or multiple malformations during prenatal ultrasound. Cases with isolated increased nuchal translucency, gamete donation and multiple pregnancies were excluded. WGS with Illumina 30X PCR‐free short‐read sequencing included the analysis of single nucleotide variants, insertions and deletions, structural variants, short tandem repeats and copy number identification of SMN1 and SMN2 genes.RESULTSA molecular diagnosis was achieved in 13/50 (26%) of cases. Causative sequence variants were identified in 12 genes: FGFR3 (n=2), ACTA1 (n=1), CDH2 (n=1), COL1A2 (n=1), DHCR7 (n=1), EYA1 (n=1), FBXO11 (n=1), FRAS1 (n=1), L1CAM (n=1), OFD1 (n=1), PDHA1 (n=1) and SOX9 (n=1). The phenotypes of the cases were divided into different groups with following diagnostic yields: skeletal 4/9 (44%), multisystem 3/7 (43%), CNS 5/15 (33%) and thorax 1/10 (10%). Additionally, two cases carried variants that were considered potentially clinically relevant even if they were assessed as variants of uncertain significance according to the guidelines provided by the American College of Medical Genetics and Genomics. Overall, we identified a causative or potentially clinically relevant variant in 15/50 (30%) of cases.CONCLUSIONSWe demonstrate a diagnostic yield of 26% with clinical WGS in prenatally detected congenital malformations. Our study emphasizes the benefits that WGS can bring to the diagnosis of fetal structural anomalies. It is important to note that causative chromosome aberrations were excluded from our cohort before WGS. As chromosome aberrations are a well‐known cause of prenatally detected congenital malformations, future studies using WGS as a primary diagnostic test, including assessment of chromosome aberrations, will most likely show that the detection rate will exceed the diagnostic yield of this study. WGS can hereby add clinically relevant information, explaining the underlying cause of the fetal anomaly, which will provide information concerning the specific prognosis of the condition as well as estimate the risk of recurrence. A genetic diagnosis can also provide more reproductive choices in future pregnancies.This article is protected by copyright. All rights reserved.