Chromosomal microarray analysis in the investigation of prenatally diagnosed congenital heart disease

Chromosomal microarray analysis has emerged as a primary diagnostic tool in prenatally diagnosed congenital heart disease and other structural anomalies in clinical practice.

Our study aimed to investigate the diagnostic yield of microarray analysis as a first-tier test for chromosomal abnormalities in fetuses with both isolated and nonisolated congenital heart disease and to identify the association of different pathogenic chromosomal abnormalities with different subgroups of congenital heart disease.

Retrospective data from 217 pregnancies that were diagnosed with congenital heart disease between 2011 and 2016 were reviewed. All pregnancies were investigated with the use of microarray analysis during the study period. Classification of chromosomal abnormalities was done based on American College of Medical Genetics and Genomics guidelines into (1) pathogenic chromosomal abnormalities that included numeric chromosomal abnormalities (aneuploidy and partial aneuploidy) and pathogenic copy number variants (22q11.2 deletion and other microdeletions/microduplications), (2) variants of uncertain significance, and (3) normal findings.

Our study found a detection rate for pathogenic chromosomal abnormalities (numeric and pathogenic copy number variants) of 36.9% in pregnancies (n=80) that were diagnosed prenatally with congenital heart disease who underwent invasive testing with chromosomal microarray. The detection rate for numeric abnormalities was 29.5% (n=64) and for pathogenic copy number variants was 7.4% (n=16) of which 4.2% were 22q11.2 deletion and 3.2% were other pathogenic copy number variants, most of which theoretically could have been missed by the use of conventional karyotype alone. Pathogenic copy number variants were most common in conotruncal defects (19.6%; 11/56) that included 42.9% in cases of interrupted aortic arch, 23.8% in cases of tetralogy of Fallot, 13.3% in cases of transposition of the great arteries, and 8.3% in cases of double outlet right ventricle. Of these changes, 81.8% were 22q11.2 deletion, and 18.2% were other microdeletions/microduplications. After conotruncal defects, pathogenic copy number variants were most common in right ventricular outflow tract and left ventricular outflow tract groups (8% and 2.2%, respectively) in which none were 22q11.2 deletion. Pathogenic chromosomal abnormalities (numeric and pathogenic copy number variants) detected by chromosomal microarray analysis were significantly more common in the nonisolated congenital heart disease group (64.5%; n=49) compared with the isolated group (22%; n=31; P<.001).

In pregnancies that were diagnosed with congenital heart disease and had undergone diagnostic genetic testing, our study showed that chromosomal microarray analysis has an added value in the detection of pathogenic chromosomal abnormalities compared with conventional karyotype, particularly in cases of pathogenic copy number variants. This yield is influenced not only by the type of congenital heart disease but also by the presence of extracardiac anomalies.