Genome sequencing in prenatal precision medicine of congenital malformations: Clinical experience from a single center

Introduction As a part of implementing genome sequencing in prenatal precision medicine at the department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden, we evaluated the utility of genome sequencing for prenatally detected malformations, including diagnostic yield, turnaround time and impact on current and future pregnancies. Material and Methods This study comprised 218 fetuses with different malformations. One hundred and two prospectively collected samples were analyzed using clinical trio genome sequencing, and if non‐diagnostic, they underwent research analysis. In addition, 116 samples were collected retrospectively and included all fetuses referred for clinical trio genome sequencing during the study period. As part of the clinical routine at the time of the study, quantitative fluorescent‐polymerase chain reaction and chromosomal microarray had been performed before genome sequencing in 84.9% (185/218) of cases. Results Clinical genome sequencing identified a molecular diagnosis in 22.5% (49/218) of the cases. Research analysis revealed two additional causative variants increasing the diagnostic yield to 23.4% (51/218). The phenotypes of the cases were divided into different groups with following diagnostic yields: 36.2% (21/58) in multisystem malformations, 30.8% (8/26) in skeletal malformations, 25.0% (14/56) in malformations in the central nervous system, 15.6% (5/32) in thoracic malformations, 11.5% (3/26) in abdominal malformations, and 0% (0/20) in other isolated anomalies. Additionally, four variants were considered potentially clinically relevant. A total of 39.2% (20/51) of the causative variants were related to a risk of recurrence. The turnaround time for clinical genome sequencing in ongoing pregnancies, when requested before gestational week 21 + 6 and prior to a parental decision on pregnancy continuation, was 12.5 ± 5 days (mean ± standard deviation, n = 40). Pregnancies with diagnostic results from genome sequencing were more likely to be terminated than those with normal results ( p = 0.012, Fisher's exact test). Conclusions Genome sequencing has an important role in prenatal precision medicine, since it can detect the underlying cause of prenatally detected malformations in a reasonable time. As causative chromosome aberrations were excluded in most of the cases, an even higher diagnostic yield can be expected if genome sequencing is offered as a first‐line test or after a normal rapid aneuploidy detection result.