Prenatal diagnosis by chromosomal microarray analysis

Abstract

Chromosomal microarray analysis (CMA) is performed either by array comparative genomic hybridization or by using a single nucleotide polymorphism array. In the prenatal setting, CMA is on par with traditional karyotyping for detection of major chromosomal imbalances such as aneuploidy and unbalanced rearrangements. CMA offers additional diagnostic benefits by revealing sub-microscopic imbalances or copy number variations that are too small to be seen on a standard G-banded chromosome preparation. These submicroscopic imbalances are also referred to as microdeletions and microduplications, particularly when they include specific genomic regions that are associated with clinical sequelae. Not all microdeletions/duplications are associated with adverse clinical phenotypes and in many cases, their presence is benign. In other cases, they are associated with a spectrum of clinical phenotypes that may range from benign to severe, while in some situations, the clinical significance may simply be unknown. These scenarios present a challenge for prenatal diagnosis, and genetic counseling prior to prenatal CMA greatly facilitates delivery of complex results. In prenatal diagnostic samples with a normal karyotype, chromosomal microarray will diagnose a clinically significant subchromosomal deletion or duplication in approximately 1% of structurally normal pregnancies and 6% with a structural anomaly. Pre-test counseling is also necessary to distinguish the primary differences between the benefits, limitations and diagnostic scope of CMA versus the powerful but limited screening nature of non-invasive prenatal diagnosis using cell-free fetal DNA.

Role of late amniocentesis in the era of modern genomic technologies

“…The higher detection rate achieved using CMA compared with karyotyping has been established both in late amniocentesis and in earlier stages of pregnancy. Here, we show that the diagnostic rate using CMA and other molecular tests was highest (17.5%) when the indication was sonographic abnormality in two or more fetal systems and the lowest (1%) for any other indication without sonographic abnormality (Figure ).…”

Prenatal chromosomal microarray testing of fetuses with ultrasound structural anomalies: A prospective cohort study of over 1000 consecutive cases

“…Standard prenatal chromosomal testing prior to the introduction of chromosome microarray (CMA) traditionally involved using quantitative fluorescent polymerase chain reaction (QF‐PCR) to exclude common autosomal and sex chromosome aneuploidies followed by a G‐banding karyotype . CMA using array comparative genomic hybridisation (aCGH) technology facilitates a greater level of variant detection to which may for specific targeted regions involve Copy number variations (CNVs) as small as 1 kb through identifying the presence of microdeletions, rearrangements, and microduplications . aCGH compares proband DNA with control samples and through hybridisation and fluorescence, identifies CNV …”

Current landscape of prenatal genetic screening and testing

“…Some CNVs are pathogenic, meaning they lead to an abnormal phenotype, and others are benign, meaning they are expected to be normal variation and not cause disease. CNVs can also have unknown significance, also referred to as variants of uncertain significance (VUS) (Levy & Wapner, ; Stosic, Levy, & Wapner, ). Additionally, some pathogenic CNVs, such as 22q11.2 deletion syndrome, can have variable phenotype with findings ranging from normal phenotype to mild‐to‐severe congenital abnormalities and/or intellectual disability.…”

“…CMA can be performed via different platforms including the oligonucleotide based array, also referred to as comparative genomic hybridization (array CGH), single nucleotide polymorphism array (SNP array), or combination of both (Levy & Wapner, ; Stosic et al, ). Both oligonucleotide and SNP platforms are able to detect CNVs that are less than 500 kb; however, the SNP array can also detect contiguous stretches of homozygosity that may be indicative of consanguinity or uniparental disomy (UPD), as well as triploidy and nonpaternity (Gardner et al, ).…”