Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder

Elizabeth A. Normand†,
Alicia Braxton†,
Salma Nassef,
Patricia A. Ward,
Francesco Vetrini,
Weimin He,
Vipulkumar Patel,
Chunjing Qu,
Lauren E. Westerfield,
Samantha Stover,
Avinash V. Dharmadhikari,
Donna M. Muzny,
Richard A. Gibbs,
Hongzheng Dai,
Linyan Meng,
Xia Wang,
Rui Xiao,
Pengfei Liu,
Weimin Bi,
Fan Xia,
Magdalena Walkiewicz,
Ignatia B. Van den Veyver,
Christine M. Eng and
Yaping YangEmail author View ORCID ID profile

†Contributed equally

Genome Medicine201810:74

https://doi.org/10.1186/s13073-018-0582-x

Received: 9 March 2018
Accepted: 12 September 2018
Published: 28 September 2018

Abstract

Background

Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting.

Methods

We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive “fetal exomes” performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher’s exact test.

Results

Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families.

Conclusion

Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.