Acknowledgements:
We would like to acknowledge the University of North Carolina Division
of Maternal Fetal Medicine and Division of Reproductive Genetics for
their support in our ongoing work in incorporation of exome and whole
genome sequencing into prenatal diagnosis.
Disclosure of Interests : The authors have no relevant
disclosures.
Contribution to Authorship: AT and NT were both equally
involved in conception, planning, and writing of this mini commentary.
Ethics Approval: n/a
Funding : NICHD K23HD088742 (PI: Vora)
Increased nuchal translucency (NT) on first trimester ultrasound poses a
diagnostic and prognostic dilemma. Given association with chromosomal
changes and other structural anomalies, an isolated increased NT is an
indication to pursue genetic diagnosis. Early diagnosis may aid
decisions for pregnancy management as a chromosomal abnormality is
identified in 30% of cases. However, with a normal chromosomal
analysis, the absence of other anomalies, and resolution of increased
NT, a healthy infant with no major anomalies results in over 95% of
cases (Bilardo et. al Ultrasound Obstet Gynecol , 2007; p11-8).
For the 70% of patients who will receive a negative chromosomal
analysis, the question arises: how can we best use advanced sequencing
to provide answers for parents, while reducing the risks of uncertainty
and decisional conflict? Prior studies have demonstrated that, at this
time, diagnostic yield is highest in the setting of negative chromosomal
microarray and presence of multiple anomalies (Lord et. al Lancet2019; p.747-57). However, beyond nomenclature and interpretation, there
have been few advances on how to best incorporate sequencing technology
into the prenatal fold. Prior studies have described institutional
approaches to integrating exome sequencing into the diagnostic paradigm
(Vora et al, Genetics in Medicine , 2020; p 1-8), and few studies
have highlighted the importance of extensive counseling and need for
additional post sequencing support given the possibility of test-related
anxiety and distress (Talati et. al, Genetics in Medicine , 2020).
As such, there is still limited guidance on how to seamlessly
incorporate sequencing into the diagnostic algorithm, particularly in
specific settings like increased NT.
In their paper, Mellis et. al attempt to answer this question. Their
group evaluated the utility of exome sequencing for (1) isolated
increased NT, or (2) increased NT in the context of multiple fetal
anomalies diagnosed in the first trimester or later in pregnancy.
Prenatal exome sequencing had a low diagnostic yield (<2%)
for isolated increased NT but the authors found that the presence of
additional anomalies in the first or second trimester dramatically
increased diagnostic yield, consistent with findings from other cohorts.
Additionally, increasing size of the nuchal translucency correlates with
improved likelihood of diagnosis, with diagnostic yield similar to the
presence of other anomalies when NT was > 7.5 mm. The
authors conclude that prenatal exome sequencing may not be
appropriate for truly isolated increased NT, but may be considered when
other anomalies are present or emerge to maximize likelihood of
diagnosis (Mellis et. al, BJOG , 2021). The study by Melliset. al contributes to a growing body of literature that informs
the clinical scenarios that benefit from sequencing strategies. However,
there are significant challenges specific to variant interpretation in
the setting of limited prenatal phenotypes and the possibility of
uncertain results. Although this study provides preliminary information,
it also reminds us of the significant work ahead to understand how the
information we present can impact pregnancy experience and management,
and most importantly, how we must first do no harm.