Findings in Chromosomal Microarray Analysis during Prenatal Diagnosis in High-Risk Individuals

Chromosomal microarray analysis (CMA) allows the detection of submicroscopic chromosomal abnormalities such as unbalanced translocations and inversions. In recent years, its use in prenatal diagnosis has been implemented when certain ultrasound findings are detected. The purpose of this study was to analyze and describe the imbalances detected in prenatal samples collected from pregnancies followed in our center for having the indication to perform diagnosis using CMA.

On a population of pregnant women of 13,685, 216 CMAs were performed on chorionic villi and amniotic fluids during the period 2019-2023. The inclusion criteria were normal screening of common aneuploidies and at least one of the following features: nuchal translucency higher than percentile 99, fetal abnormalities, early-onset fetal growth restriction, parents' history of chromosomal imbalances, or cases with chromosomal imbalances. When a relevant variant was detected, it was analyzed in the parents' fetus and when available, the phenotype of the born children was collected.

Pathogenic copy number variations (CNVs) were detected in 13 of 216 samples (6%). In a single sample, two concurrent CNVs were detected. Isolated CNVs had OMIM numbers and corresponded to already reported syndromes. Seven variants of unknown significance (3.7%) were observed. The study of the parents showed that 14 of 21 variants identified had arisen de novo (one pathogenic and five unknown CNVs had been inherited from an apparently healthy parent). Three microduplications specially drew our attention: duplication 5q35.2 which encompassed MSX2 gene (because the reported phenotype is not consistent with what is expected for the genomic region) and duplications 1q21.1 and 16p11.2 (due to the ultrasound findings detected in fetuses had recently been postulated to be associated with these CNVs).

The phenotype of CNVs identified in prenatal samples is highly variable prenatally, like postnatally. Some findings may be part of the syndromes to which they give rise and some phenotypes may be pending to define. Further studies are needed to better define these variants and to understand how haploinsufficiency or over-expression of genes included in these regions can cause such complex phenotypes.