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.