Universal chromosomal microarray analysis reveals high proportion of copy‐number variants in low‐risk pregnancies

Abstract

What are the novel findings of this work?We calculated the rate of clinically significant chromosomal microarray analysis (CMA) findings in low-risk pregnancies, i.e. pregnancies with normal ultrasound (US) at the time of genetic testing, and found that the rate was relatively high. In addition, we documented later-appearing abnormal US findings and pregnancy outcome in these cases. What are the clinical implications of this work?The findings of this study allow an in-depth understanding of the yield of CMA and the impact of CMA results in pregnancies with normal US at the time of genetic testing. This may affect policy regarding CMA for low-risk pregnancies as well as counseling for prospective parents regarding the test and its possible results.

What is the meaning of a ‘genomic result’ in the context of pregnancy?

“…The chances of identifying variants with uncertain clinical significance and/or lowpenetrant susceptibility loci in these uneventful pregnancies will often be higher than Defining results from genome testing in pregnancy 10 the chance of identifying variants that would clearly have a severe impact on health in childhood (2).…”

Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis

“…In particular, low‐level mosaicism (<15%‐20%), foetal‐placental discrepancies and the UPD generated by embryo rescue have been reported to be responsible for the increased risk of erroneous diagnoses 4,5 . Recently, improvements have been made in the field of molecular genetics technologies such as quantitative fluorescent polymerase chain reaction (QF‐PCR), fluorescence in situ hybridization analysis (FISH), CMA and next‐generation sequencing so that supplementary analyses on amniotic fluid or cord blood are often performed to confirm the true foetal involvement and its clinical significance 6‐10 . Nevertheless, even CM thought to be confined to the placenta may reflect a cryptic foetal mosaicism that may or may not give rise to phenotypic consequences, or lead to placental dysfunction related to foetal growth restriction 11,12 …”

“…4,5 Recently, improvements have been made in the field of molecular genetics technologies such as quantitative fluorescent polymerase chain reaction (QF-PCR), fluorescence in situ hybridization analysis (FISH), CMA and next-generation sequencing so that supplementary analyses on amniotic fluid or cord blood are often performed to confirm the true foetal involvement and its clinical significance. [6][7][8][9][10] Nevertheless, even CM thought to be confined to the placenta may reflect a cryptic foetal mosaicism that may or may not give rise to phenotypic consequences, or lead to placental dysfunction related to foetal growth restriction. 11,12 Thus, based on the unclear clinical significance of CM and limited data about CM in prenatal diagnosis, it is necessary to understand more comprehensively the potential correlation between CM and its phenotypic effects.…”

Do we need to rethink our standard genetic approach for low‐risk pregnancies?

“…A recent study by Stern and colleagues found that 1% of a-priori low-risk pregnancies could have an abnormal chromosomal microarray analysis (CMA) result 1 . These findings are congruent with those of previous studies 2 and raise the question of the optimal genetic approach for low-risk pregnancies.…”