(193) Prenatal deep phenotyping using ultrasound and MRI improves the diagnostic yield of exome sequencing

To evaluate whether comprehensive prenatal deep phenotyping increases the diagnostic yield of exome sequencing in fetuses with anomalies where QF-PCR and chromosomal microarray testing were non-diagnostic.

Study Design:

We conducted a prospective cohort study of cases referred to our department over a four-year period for consideration of further genetic testing due to a suspected fetal anomaly. All cases had previously undergone QF-PCR and chromosomal microarray with no molecular diagnosis identified. Selected cases underwent prenatal deep phenotyping. This was defined as detailed, multidisciplinary evaluation of the fetal phenotype using ultrasound, MRI or both to guide further genetic testing.

Results:

A total of 109 patients met the inclusion criteria. The phenotypes seen were multisystem anomalies in 45% (n=49), musculoskeletal in 22% (n=24), neurological in 11.9% (n=13), fetal hydrops in 6.4% (n=7), cardiac in 4.6% (n=5), cystic hygroma and gastrointestinal in 3.7% (n=4), renal in 1.8% (n=2) and face in 0.9% (n=1).

An overall molecular diagnosis was achieved in 51.4% of cases (n=56). Of the 109 cases, 34 underwent deep phenotyping by ultrasound, MRI or a combination of the two. Among the 34 cases who underwent deep phenotyping, 74% (n=25) received a molecular diagnosis, compared to 41% (n=31) of the 75 cases who did not undergo deep phenotyping. This difference was statistically significant (p=0.002), indicating that deep phenotyping was associated with an increased diagnostic yield in this cohort.

Conclusion:

Prenatal deep phenotyping using ultrasound and/or MRI is significantly associated with a higher rate of molecular diagnosis. This supports its value in the evaluation of fetal anomalies with inconclusive preliminary genetic testing.