Genetic assessment for CHD: Case-specific, stepwise

A personalized approach

There has been growing interest in recent years in CMA for the prenatal genetic workup of CHDs. Microarray targets chromosomal regions at a much higher resolution than traditional karyotype. Traditional karyotype assesses both changes in chromosome number as well as more subtle structural changes such as chromosomal deletions and duplications. CMA finds what traditional karyotype identifies, but in addition, it identifies much smaller, clinically relevant chromosomal deletions and duplications that are not detected by karyotype performed with or without fluorescence in-situ hybridization (FISH). FISH uses DNA probes that carry fluorescent tags to detect chromosomal DNA.

^{Source: Dr. Shifa Turan}

At our center, we studied the prenatal genetic test results of 145 fetuses diagnosed with CHDs. Each case involved FISH for aneuploidy/karyotype, followed by CMA in cases of a negative karyotype result. CMA increased the diagnostic yield in cases of CHD by 19.8% overall – 17.4% in cases of isolated CHD and 24.5% in cases of CHD plus extracardiac anomalies.⁴

Indeed, although a microarray costs more and takes an additional 2 weeks to run, CMA should be strongly considered as first-line testing for the prenatal genetic evaluation of fetuses with major structural cardiac abnormalities detected by ultrasound. However, there still are cases in which a karyotype might be sufficient. For instance, if I see that a fetus has an atrial-ventricular septal defect on a prenatal ultrasound, and there are markers for trisomy 21, 13, or 18, or Turner’s syndrome (45 XO), I usually recommend a karyotype or FISH rather than an initial CMA. If the karyotype is abnormal – which is likely in such a scenario – there isn’t a need for more extensive testing.

Similarly, when there is high suspicion for DiGeorge syndrome (the 22q11.2 deletion, which often includes cleft palate and aortic arch abnormalities), usually it is most appropriate to perform a FISH test.

CMA is the preferred first modality, however, when prenatal imaging suggests severe CHD – for instance, when there are signs of hypoplastic left heart syndrome or tetralogy of Fallot (a conotruncal defect) – or complex CHD with extracardiac anomalies. In these cases, there is a high likelihood of detecting a small deletion or duplication that would be missed with karyotype.

In the past decade, karyotype and CMA have become the major methods used in our practice. However, targeted next‐generation sequencing and whole‐exome sequencing may become more widely used because these technologies enable rapid analysis of a large number of gene sequences and facilitate discovery of novel causative genes in many genetic diseases that cause CHDs.

Currently, targeted next-generation sequencing has mainly been used in the postnatal setting, and there are limited data available on its prenatal use. Compared with whole-exome sequencing, which sequences all of the protein-coding regions of the genome, targeted next-generation sequencing panels select regions of genes that are known to be associated with diseases of interest.

For CHDs, some perinatal centers have begun using a customized gene panel that targets 77 CHD-associated genes. This particular panel has been shown to be useful in addition to current methods and is an effective tool for prenatal genetic diagnosis.⁵

Whole-exome sequencing is currently expensive and time consuming. While sometimes it is used in the postnatal context, it is not yet part of routine practice as a prenatal diagnostic tool. As technology advances this will change – early in the next decade, I believe. For now, whole-exome sequencing may be an option for some patients who want to know more when severe CHD is evident on ultrasound and there are negative results from CMA or targeted sequencing. We have diagnosed some rare genetic syndromes using whole-exome sequencing; these diagnoses helped us to better manage the pregnancies.

^{Source: Dr. Shifa Turan}

These choices are part of the case-specific, stepwise approach to genetic evaluation that we take in our fetal heart program. Genetic investigation in CHDs has great potential to improve prognosis with personalized medical care, but we need to be thoughtful about what tests we pursue. Our goal is to pursue information that will be accurate and valuable for the patient and clinicians, in the most cost-effective and timely manner.