The Diagnostic Yield of Prenatal Genetic Technologies in Congenital Heart Disease: A Prospective Cohort Study

<b><i>Introduction:</i></b> The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). <b><i>Methods:</i></b> This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in <i>n</i> = 147 cases of prenatally diagnosed CHD was assessed. <b><i>Results:</i></b> In 34.7% (<i>n</i> = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (<i>n</i> = 23/147), 13.7% (<i>n</i> = 17/124), and 10.2% (<i>n</i> = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (<i>n</i> = 11/35), <i>p</i> = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (<i>n</i> = 10/44), <i>p</i> = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (<i>n</i> = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1–5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (<i>n</i> = 5/107) with ES, with none in the CMA group. <b><i>Conclusion:</i></b> In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.