Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

Abstract

Objective: To determine the perinatal outcomes of fetuses diagnosed with a pathogenic copy number variant (CNV) or variant of uncertain significance (VUS); and to characterize these variants in terms of testing indication, genomic location, size, and inheritance. Methods:Retrospective study of singleton pregnancies with a pathogenic CNV or VUS from a single laboratory during 2012-2018. Probabilistic record linkage between the prenatal diagnosis dataset and perinatal outcome data for births from 20 weeks gestation was performed. If no birth record was found, this implied a pregnancy loss <20 weeks. Results:We included 6945 prenatal microarray results; a pathogenic CNV was detected in 230 (3.3%, 95% CI: 2.9%-3.8%) and a VUS in 483 (7.0%, 95% CI: 6.4%-7.6%). Of pregnancies with a pathogenic CNV, 20.0% (95% CI: 15.3%-25.6%) had a live birth, 3.0% (95% CI: 1.5%-6.2%) had a perinatal death (stillbirth or neonatal death), and 77% (95% CI: 71.1%-81.9%) had no birth record. Of those with a VUS, 64.4% (95% CI: 60.0%-68.5%) had a live birth, 1.8% (95% CI: 1.0%-3.5%) had a perinatal death, and no birth record was found for 33.7% (95% CI: 29.7%-38.1%).Most pathogenic CNVs (61.1%) were <7 Mb in size. The most common microdeletion syndromes were DiGeorge, Wolf-Hirschhorn, and Cri-du-chat syndromes. Conclusion:This study provides an overview of perinatal outcomes and frequency of recurrent CNVs observed in the prenatal microarray era. Key points What is already known about this topic?� Fetal copy number variants (CNVs) detected on chromosomal microarray have a wide range of clinical significance.� Large studies reporting perinatal outcome rates after a prenatal diagnosis of a CNV are rare.

Position statement from the International Society for Prenatal Diagnosis on the use of non‐invasive prenatal testing for the detection of fetal chromosomal conditions in singleton pregnancies

“…The three most common microdeletion syndromes in the prenatal diagnosis population are 22q11.2 deletion syndrome (DiGeorge syndrome), 4p16.3 deletion (Wolf‐Hirschhorn syndrome) and 5p15.33 deletion syndrome (Cri‐du‐Chat syndrome) 76 . MMS are not detectable with traditional aneuploidy screening tests and are not related to maternal age.…”

“…More than half of the pathogenic CNVs in the prenatal diagnosis population are <7 Mb in size and thus below the resolution of many current genome-wide NIPT platforms. 76 The use of NIPT for sub chromosomal imbalances continues to be debated due to the risks of false positives, increasing parental anxiety, and potentially increasing diagnostic procedures. 39,77 In selected circumstances, however, it may be of clinical utility, for example, for carriers of balanced reciprocal translocations.…”

A decade of non‐invasive prenatal screening in Australia: National impact on prenatal screening and diagnostic testing

“…The popularity of NIPT is also responsible for the historically low rates of prenatal diagnostic procedures, now sitting at 2–3% of all births in Victoria 5,6 . NIPT has the highest diagnostic yield of any indication for prenatal diagnostic procedures (62.2%), three times higher than combined first trimester screening (19.8%) 6 .…”

“…The popularity of NIPT is also responsible for the historically low rates of prenatal diagnostic procedures, now sitting at 2–3% of all births in Victoria 5,6 . NIPT has the highest diagnostic yield of any indication for prenatal diagnostic procedures (62.2%), three times higher than combined first trimester screening (19.8%) 6 . Despite the clinical benefits and popularity of NIPT, all three previous applications for a Medicare item number have failed largely on cost effectiveness grounds (Medical Services Advisory Committee applications #1458, 1461, 1492) 14 .…”

“…Victorian state‐wide data show that the three most common indications for diagnostic testing over the past five years were ultrasound abnormality, NIPT result, and single gene testing, in that order 6 . However, this steady state may not last long.…”