A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort

Abstract

STUDY QUESTION What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA. The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births. LIMITATIONS, REASONS FOR CAUTION Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected. WIDER IMPLICATIONS OF THE FINDINGS Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS. STUDY FUNDING/COMPETING INTEREST(S) L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children’s Research Institute has supported the prenatal diagnosis data collection and reporting over the years. Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work. TRIAL REGISTRATION NUMBER NA

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross‐sectional study with healthcare professionals

“…A further consideration is how we define and categorise VUS. For example, 22q11 duplication may be called a VUS in some countries, 9 and a pathogenic variant of low penetrance or a susceptibility loci in others 2,39 . The guidelines are also nondirective on this matter; for example, for 22q11 duplication the UK Royal College of Pathologists says ‘Consider detailed scan looking for associated anomalies or reporting in a clinical context’ 26 .…”

“…Although uncertainty in the prenatal setting is not new, the scale and types of uncertainty that may occur is increasing because of the more detailed comprehensive analysis of the fetal genome. For example, detection of VUS has been reported in around 2%–6% of prenatal cases through CMA 2,7–9 and around 4%–20% of cases through ES, 3,10,11 although the proportion is likely to decrease as new knowledge is gained and VUS are reanalysed 11 …”

The difference between karyotype analysis and chromosome microarray for mosaicism of aneuploid chromosomes in prenatal diagnosis

“…Newborns with congenital diseases can increase the physical and mental burden on a family and the parents 1 . Chromosomal abnormalities are the main cause of congenital diseases, which can be manifested as multiple malformations, including physical and mental development disorders and other serious clinical symptoms 2–4 .…”

Fetal and Neonatal Autopsy in the Molecular Age: Exploring Tissue Selection for Testing Success

“…Karyotype is the most affordable testing option and, if culture is successful (74% in this cohort), can detect aneuploidy and polyploidy which account for greater than 50% of genetic anomalies in stillbirth. 19 However, karyotyping requires time-consuming tissue culture from viable cells and is more likely to fail in cases of intrauterine demise compared to chromosomal microarray. 11,20 However, CMA is unable to recognize balanced alterations and translocations with two copies of each loci, even when transferred to another chromosomal location.…”