Evaluating Prenatal Exome Sequencing Study

Foetal anomalies as detected on prenatal ultrasound are present in 2-3% of
pregnancies. The diagnosis of a genetic syndrome as the underlying cause often
has significant consequences for the prognosis and therefore also a significant
impact on parental reproductive decision making. In addition to chromosomal
testing, prenatal exome sequencing (pES) is increasingly being offered.
Although prenatal diagnostic rates are promising, no studies report on the
actual implementation of pES in routine care and thus several important
knowledge gaps remain regarding clinical utility (the balance between potential
harms and benefits) and the preferred analysis strategy (broad versus targeted
analysis). A broad analysis has a possible higher diagnostic yield, but it is
unknown whether the increased chance of finding a probable diagnosis (class 4
or 5 according to the American College of Medical Genetics but with an unclear
or partial correlation to the prenatal phenotype, or class 3 with a
multidisciplinary consensus on a strong possibility of clinical relevance) and
Incidental Findings outweighs this benefit when it comes to clinical decision
making and parental psychological wellbeing.

This study evaluates the impact of the various outcomes of prenatal exome
sequencing (definitive diagnosis, probable diagnosis and incidental findings)
on clinical decision making and on parental psychological wellbeing, compared
between different analysis strategies to investigate the clinical utility,
defined as the balance between potential harms and benefits.

This study will be a multicenter cohort study with prospective data collection.
Patients will be informed about the study during their first consultation at
the Clinical Genetics department. The clinical geneticist or the researcher
(PhD candidate) will then provide the patient information letter and will get
informed consent. Data will be collected from exome analysis, medical records
and for live born children we will request medical information from the Dutch
pediatric public healthcare system. Online questionnaires will be sent at (Q1)
the time of inclusion, (Q2) 1-2 weeks after pES result and (Q3) 6-8 weeks after
delivery or termination of pregnancy.

In a small subset of patients of the LUMC (target n = 15), two additional
interviews will be conducted by telephone in parallel to the quantitative
questionnaires. These interviews contain similar questions as the
questionnaires. After verbal informed consent is received, the researcher will
contact the participants in the time period between the initiation of pES and
the return of results for the first interview. The second interview will take
place approximately 6 months after the results were shared with patients. The
coded interview data will be analyzed together with the interview data of a
similar research cohort in Australia (called 'PreGen').

Since the study subjects are capacitated adults who will be asked to fill in
questionnaires and possibly participation in interviews by phone, no risks are
present. Potential burdens are;
1. Additional time patients need for filling in the questionnaires
(approximately one hour spread out over one year) and the possible interviews
by phone (approximately one and a half hour spread out over six months).
2. Psychological discomfort due to the sensitive questions regarding, amongst
others, decisional regret about testing and the choice of pregnancy outcome.
These potential burdens are in proportion to the scientific value of the
potential outcomes of this research, especially since the results will be used
to reduce psychological discomfort in future patients.