How can prenatal exome sequencing inform future pregnancies?

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.¹ 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.² 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).³ 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.⁴ 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.

TABLE.

Fetal ultrasound findings, sequencing result, variant interpretation, and method of prenatal diagnosis in subsequent pregnancy

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

CVS, chorionic villus sampling; IUGR, intrauterine growth restriction; LP, likely pathogenic; PGT, preimplantation genetic testing; PGT-M, preimplantation genetic testing for monogenic disorders; P, pathogenic; VUS, variant of uncertain significance.

Talati. Exome sequencing and future pregnancies. Am J Obstet Gynecol 2022.

All the participants provided pre- and post-ES comments. Pre-ES, 4 of them hoped to identify an etiology for pregnancy loss (eg: “we hope to understand why we lost the baby”); 1 described a search for closure, (“to get closure if there is an answer”); and 1 wanted information for future diagnosis (“guidance for future pregnancy testing”). Post-ES, 4 responded positively to the results (eg, “We now know the mutation we had. It’s good that we know so we’re not caught off guard in the future”).

CONCLUSIONS:

Although limited in sample size, our report demonstrates that receiving ES results impacts future pregnancy diagnostic decisions. However, this report is not without limitations. First, ES demonstrates a diagnostic yield of 15% to 19% when multisystem anomalies are present and standard testing is negative.¹ Thus, most of the individuals had nondiagnostic results and did not contact us. Second, individuals in this report had access to early prenatal diagnosis. It is unlikely that ES would confer the same opportunity to those with barriers to care. Furthermore, the time to receive results with ES may be weeks. It requires complex genetic counseling and is costly; as such, its use for pregnancy management decisions in an ongoing pregnancy is uncertain.⁵ Finally, 1 person in our cohort had diagnostic testing on the basis of a variant of unknown significance (VUS), identifying an area where guidelines are unclear and decisions may be driven by test-related anxiety and distress.⁴ Given our expanding testing but limited correlation with the fetal phenotype and the significant distress associated with a diagnostic vs nondiagnostic result,⁴ providers should recognize that there is currently no specific guidance on how a VUS may inform future pregnancy decisions, and this should be an area of focus for future studies.