OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Further, the performance of combined first-trimester screening (cFTS) in detecting affected pregnancies and a new risk algorithm specifically for 22q11.2 deletions will be evaluated. Finally,, the prevalence of prenatal malformations and pregnancy outcomes will be assessed.

METHODS: We conducted a nationwide register-based cohort study on all pregnancies seen for prenatal screening with due dates between January 2008 and December 2018. All cases with a fetal 22q11.2 deletion or -duplication [hg19 chr22:18.8mio-23.7mio] diagnosed pre- or postnatally, following pregnancy loss, or following termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal medicine Database. Fetal and maternal characteristics including cFTS data and pregnancy outcome in all deletions and duplications (LCR22-A to -H) and in classic deletions and duplications (LCR22-A to -D) diagnosed by chromosomal microarray were compared to a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A, and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated.

RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration (97 deletions (54 classic) and 46 duplications (32 classic)). Nuchal translucency was significantly increased in fetuses with a classic deletion (mean 1.89 mm), any deletion (mean 1.78 mm), and any duplication (mean 1.86 mm) compared to the reference group (mean 1.65 mm). β-hCG MoM was decreased in all subgroups and reached significance in pregnancies with a classic deletion as well as any deletion (mean 0.77 and 0.71) compared to the reference group (mean 1.02 MoM). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication (mean 0.57) and any duplication (mean 0.63) whilst in pregnancies with a classic deletion and any deletion, PAPP-A MoM was significantly increased (mean 1.34 and 1.16) (mean 1.01 in reference pregnancies). The screen positive rate from cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%), or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletion but with a substantial increase in the false positive rate. Structural malformations werae detected in 41%, 35%, 17%, and 25% of the pregnancies with a classic deletion, any deletion, classic duplication, or any duplication, respectively. Pregnancy loss occurred in 40% of the pregnancies with a classic deletion and in 5% of the pregnancies with a classic duplication diagnosed prenatally or following pregnancy loss.

CONCLUSION: The cFTS markers in pregnancies with a classic 22q11.2 duplication resembles the common trisomies with decreased levels of PAPP-A. The classic 22q11.2 deletions, however, have increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions from targeted risk algorithms using NT, PAPP-A, and β-hCG seems limited. This demonstrates the capability, but also the limitations, of the cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. This article is protected by copyright. All rights reserved.