Fetal phenotype.
The two prospective studies recruited pregnancies in which the fetus had an ultrasound identified abnormality and the fetal medicine specialist believed was worthy of antenatal karyotyping (QF PCR / CMA). Both studies therefore were pragmatic in the identification of an unselected cohort of fetuses with structural malformations in a routine fetal medicine clinical setting27,28. The consequence of this was a heterogeneous mix of anomalies. Both studies recruited a high proportion of fetuses with multiple (>1) structural anomalies and the Petrovski study had a proportion of pregnancies included where there was a strong suspicion of ‘genetic disease’ (i.e. identification of skeletal dysplasia, cardiac rhabdomyoma; infantile polycystic kidneys)28. Both studies found a greater diagnostic rate of pathogenic variants in the presence of multiple congenital anomalies (between 15.4% - 18.9% respectively)27,28. This opens a debate as to whether to specifically select fetuses with specific single anomalies and/or greater than two major abnormalities for testing, and if testing should be broad (i.e. ES) or based upon a “targeted “virtual panel dependent on the presenting phenotype. High resolution ultrasound has led to the diagnosis of structural anomalies in the fetus with variable rates of detection29, even with the use of additional modalities such as magnetic resonance imaging30. Subtle dysmorphic features may not be diagnosed and variability of phenotypic expression, incomplete penetrance and varying gestation of presentation make the identification of the fetus at risk of monogenic disorders challenging. Case selection of prenatally identified abnormal fetuses, after genetics review and additional phenotypic information from autopsy are two independent factors that increase diagnostic yield31,32. Published post-mortem series suggest a yield from ES of up to 30%, reflecting the importance of case selection, and detailed, accurate phenotyping (with the inclusion of subtle dysmorphic features)10,23,33. In addition, it is not just the identification of abnormalities that may be important. In childhood, the identification of neurodevelopmental and intellectual disability (not definable prenatally) may also indicate the potential underlying aetiology (Yang Y et al, 2013; DDD Study, 2015). The PAGE study identified specific phenotypes associated with the highest association of pathologic variants and these included multiple anomalies (15.4%), anomalies of the skeletal (15.4%), cardiac (11.1%) and spinal systems (10%) as well as the presence of non-immune fetal hydrops(9%) (Figure 1). After correction for multiple testing, the detection of pathologic (or likely pathogenic) variants in a fetuses with multisystem anomalies was significantly more likely than in fetuses with any single abnormality (p=0.018)27. The Petrovski study demonstrated a similar association with structural phenotype; however renal anomalies (several fetuses with infantile polycystic disease) were associated with significant monogenic disease (16%)28. From the PAGE study, large nuchal translucencies (>4mm) had a relatively low association with identifying a pathologic variant (unless on subsequent scanning at 20 weeks additional anomalies were identified)34.
It should also be recognised that prenatal and postnatal phenotypes may differ with the same underlying genetic pathologic variant. A good example of this is in the presence of mutations in the histone methyltransferase KMT2D and the demethylase KDM6A (of which multiple variants are known)35 being associated with Kabuki syndrome. In childhood, this is characterised by classic facial gestalt, multiple organ malformations, abnormal postnatal growth and intellectual morbidity36. In prenatal life, it appears associated with nuchal oedema, hydrops fetalis, cardiac malformations, intrauterine growth restriction and stillbirth27,28.