Prenatal Genetic Diagnosis by Genomic Sequencing

Whole exome and whole genome sequencing (WGS) have expanded the ability to determine the genetic etiology of previously undiagnosed disorders. This study is a multicenter prospective cohort study to evaluate the emerging technology of sequencing for the management of fetuses with structural anomalies. The hypothesis is that a significant subset of fetal structural anomalies has a genetic etiology identifiable by sequencing and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. The aims of this study are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting.

The study will determine, in a sequential population of pregnancies with selected fetal structural anomalies and a negative or non-causal chromosomal microarray (CMA), the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by sequencing. To determine the impact of this information on clinical care, a control population of unsequenced pregnancies with similar structural anomalies will be prospectively recruited and the infants from both cohorts will be followed up to 1 year of age. This study component will evaluate differences in healthcare management and cost through discharge from hospital post-delivery, and perinatal and infant outcomes through 1 year of life. The educational, counseling and psychosocial impact of sequencing results during the prenatal period, in the nursery and through 1 year of life also will be evaluated. Since the analytical and clinical tools needed for the full translation of sequencing into care are still developing, optimization of bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes will be investigated, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. This study will provide an in-depth evaluation of the prenatal diagnostic value of sequencing prior to its responsible introduction into practice and will provide independent data to guide its translation.

Inclusion criteria

Prenatal sequencing group

• Fetus identified by ultrasound and/or MRI with at least one of the following:

• One or more major structural anomalies (Appendix A)
• A nuchal translucency measurement of ≥ 3.5 mm
• A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth.
• Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding)
• Singleton or twin gestation
• Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery

Unsequenced Group

• Fetus identified by ultrasound and/or MRI with at least one of the following:

• One or more major structural anomalies (Appendix A)
• A nuchal translucency measurement of ≥ 3.5 mm
• A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth
• Negative prenatal or postnatal CMA (or those with CMA findings not related to the ultrasound finding)
• Declined prenatal sequencing
• Singleton gestation

Exclusion criteria

Prenatal Sequencing Group

• Prenatal sequencing or planned prenatal sequencing performed outside of the study, including gene panels
• Maternal or paternal age less than 18 years old
• Proven infectious or teratogenic cause of fetal anomaly
• Planned termination of the pregnancy
• Unavailable blood or saliva samples from both biologic parents prior to sequencing
• Parental unwillingness to participate in 1 year postnatal follow-up
• Language barrier (non-English or Spanish speaking)
• Previous consent to the unsequenced prenatal group or enrollment in a previous pregnancy

Unsequenced Group

• Maternal or paternal age less than 18 years old
• Proven infectious or teratogenic cause of fetal anomaly
• Positive prenatal NIPT screening for trisomy 21,18 or 13. Positive 22q11.2 prenatal NIPT testing with consistent ultrasound findings is also an exclusion.
• Planned termination of the pregnancy
• Parental unwillingness to participate in 1 year postnatal follow-up
• Language barrier (non-English or Spanish speaking)