Objective
Exome sequencing (ES), or sequencing of the protein coding regions of the genome, has revolutionized medicine and offers significant promise for prenatal diagnosis. Current studies emphasize the technical feasibility of ES. However, exploring the future impact of ES is critical to using this technology for fetal diagnosis. In particular, how ES informs future reproductive decisions has been understudied. The objective of this study is to report how parents used diagnostic results from trio ES during an anomalous pregnancy to inform future diagnostic decisions.
Study Design
This was a case series of select patients in a prospective trio (sequencing of both parents and fetus) ES study (institutional review board grant number 13-4084) from July 2014 to July 2021. The study was eligible to patients with an anomalous pregnancy and nondiagnostic standard genetic testing (protocol provided in the Reference). Following participation, some elected to provide information regarding subsequent pregnancies. Notably, this was volunteered by and was not systematically ascertained from all the participants. Data presented in this report include (1) postsequencing comments part of the study protocol and (2) volunteered information regarding future pregnancies.
Results
Overall 126 trios have been sequenced. Of those, 6 participants volunteered information on testing decisions in subsequent gestations. Notably, all 6 terminated the enrolled pregnancy and used ES diagnostic information in the next gestation (amniocentesis/chorionic villus sampling or preimplantation genetic testing for monogenic disorders) ( Table ). Other pregnancies may have occurred within the cohort but were not reported to the study personnel.
| ID # | Ultrasound-detected fetal anomaly | Sequencing result | Variant interpretation | Prenatal diagnosis in subsequent pregnancy |
|---|---|---|---|---|
| 1 | Nonimmune hydrops | Compound heterozygous PIEZO1 variants | LP/VUS | CVS |
| 2 | Cystic hygroma, omphalocele, broad abducted thumbs, hydrops, hydrocephalus, hypoplastic cerebellum, Chiari malformation | Compound heterozygous WDR81 variants | LP/LP | Amniocentesis |
| 3 | Micrognathia, heart defect, hypotonia. dysmorphic facial features, sacral dimple | De novo KMT2A variant | LP | PGT-M |
| 4 | Arthrogryposis, hypoplastic right heart, enlarged liver, polyhydramnios | De novo HRAS and compound heterozygous HEXB variants | LP/LP ( HEXB ) LP ( HRAS ) | CVS |
| 5 | Sloping forehead, micrognathia, IUGR, ambiguous genitalia, abnormal renal arteries, arthrogryposis | Compound heterozygous TRAIP variants | P/VUS | CVS |
| 6 | Fixed abnormally positioned upper extremities, rocker bottom feet | Homozygous ADGRG6 (aka GPR126) variant | VUS/VUS | PGT |
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