Increased prenatal detection of 22q11.2 deletion and 22q11.2 duplication after introduction of nationwide prenatal screening for trisomy 21, trisomy 13, and trisomy 18

Abstract

Objective To evaluate time of diagnosis of 22q11.2 deletion and 22q11.2 duplication as well as trisomies 21, 13, and 18 before and after introduction of a prenatal screening program including combined first‐trimester screening (cFTS) for the trisomies in Denmark in 2004. Method Cross‐sectional, population‐based register study employing The Danish Cytogenetic Central Register. Proportions of cases diagnosed 1998‐2004 and 2005‐2017 were compared before 14+0 and 22+0 weeks and birth (prenatal cases) or up to 1 or 10 years of age (postnatal cases). Results In total, 4562 cases were included. From 1998‐2004 to 2005‐2017, the proportion of 22q11.2 deletion cases identified prenatally increased from 4.3% (95% CI: 0.9‐12.0%) to 27.3% (21.2‐34.0%), while for 22q11.2 duplication an increase from 0/6 to 26/87 (prenatal cases/all cases) was observed. Similarly, proportions of trisomies 21, 13, and 18 detected before birth increased. A greater proportion of the studied conditions was identified earlier in pregnancy, but not generally earlier in the postnatal course. Conclusion Proportions of 22q11.2 deletion and 22q11.2 duplication identified prenatally increased after introduction of a prenatal screening program not aimed specifically to identify these conditions,. A greater proportion of all cases were detected earlier in pregnancy, but not earlier postnatally, following introduction of screening.

Decoding 22q11.2: prenatal profiling and first‐trimester risk assessment in Danish nationwide cohort

“…Similarly, in an Australian cohort of 100 418 women who underwent cFTS, 44% (45/102) of atypical anomalies (including pathogenic CNVs) occurred in women with a risk of trisomy 21 on cFTS of greater than 1 in 300 23 . Furthermore, we demonstrated recently how the introduction of the national Danish prenatal screening program in 2004 increased the prenatal detection of 22q11.2 deletions and duplications from 3.9% (1998-2004) to 28% (2005-2017) 4 . However, CNV detection by cFTS is limited to cases in which the distribution of cFTS parameters resembles that of one of the major trisomies.…”

“…Microdeletions and microduplications in the 22q11.2 region are some of the most commonly occurring CNVs. In neonates, 22q11.2 microdeletions alone are more common than are trisomies 13 and 18 combined, with a prevalence estimated at 1 in 4000 to 8000 live births 4,5 . 22q11.2 aberrations cause a wide spectrum of clinically significant conditions, and, after trisomy 21, the microdeletion is the most common genetic cause of developmental delay and congenital heart malformation 3,6,7 .…”

Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017

“…Our study included a large nationwide and unselected cohort of singleton pregnant women with virtually complete information on pregnancy outcomes, thereby minimizing selection bias 27 . Moreover, the very high participation rate in first‐trimester screening in Denmark contributed to a highly representative study population, and our findings therefore apply to the general population of pregnant women.…”

Atypicality index as an add‐on to combined first‐trimester screening for chromosomal aberrations

“…A meta-analysis estimated the background risk of submicroscopic aberrations to be 1 in 270 4 , which is comparable to our results of 1 in 328 (with 2 years of postnatal follow-up). The exact detection of pCNVs by cFTS is uncertain, but it is estimated to be 25-50% 3,6,[22][23][24] . In our cohort, only 15% of the pCNVs screened positive using the risk cut-offs previously specified, and 46% were not diagnosed until after birth.…”

“…Furthermore, the phenotype is often severe, as seen in Smith-Magenis syndrome, Wolf-Hirschhorn syndrome and 22q11 deletion syndrome 5 . cFTS is not designed to identify chromosomal aberrations other than the common trisomies, which is why a large proportion of these atypical submicroscopic aberrations are not detected from a high-risk cFTS result early in pregnancy 3,6 .…”