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. 2018 Sep 28;10(1):74.
doi: 10.1186/s13073-018-0582-x.

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

Elizabeth A Normand  1 , Alicia Braxton  1   2 , Salma Nassef  1 , Patricia A Ward  1   2 , Francesco Vetrini  2 , Weimin He  2 , Vipulkumar Patel  2 , Chunjing Qu  2 , Lauren E Westerfield  1 , Samantha Stover  1 , Avinash V Dharmadhikari  2 , Donna M Muzny  1   3 , Richard A Gibbs  1   3 , Hongzheng Dai  1 , Linyan Meng  1   2 , Xia Wang  1   2 , Rui Xiao  1   2 , Pengfei Liu  1   2 , Weimin Bi  1   2 , Fan Xia  1   2 , Magdalena Walkiewicz  1   2   4 , Ignatia B Van den Veyver  1   5 , Christine M Eng  1   2 , Yaping Yang  6   7
Affiliations

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

Elizabeth A Normand et al. Genome Med. .

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.

Keywords: Exome sequencing; Fetal structural abnormalities; Mendelian disease; Prenatal; Single-gene disorder.

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Conflict of interest statement

Ethics approval and consent to participate

De-identified reporting of demographic and molecular data from this laboratory was approved by the Institutional Review Board at Baylor College of Medicine. For clinical testing, all exome tests involving a fetal sample required informed consent, which was obtained from parents. This research conformed with the principles of the Declaration of Helsinki.

Consent for publication

Not applicable

Competing interests

IBVdV is a member of the Baylor Genetics scientific advisory board, but receives no direct compensation for this role.

YY is on the Scientific Advisory Board of Veritas Genetics China. YY and XW founded AiLife Diagnostics, Inc. FV, WH, VP, CQ, AVD are/were employees of Baylor Genetics.

The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from genetic testing offered at Baylor Genetics. The remaining authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Molecular diagnostic rates based on phenotype. a Molecular diagnostic rate is higher in fetuses with abnormalities affecting multiple organ systems (p = 0.018; see Additional file 1: Table S5 for non-significant group comparisons). The number of fetuses in each category is indicated on the relevant bar graph. Each top-branch category was only counted once per fetus. b Molecular diagnostic rates are shown for fetuses with (+) or without (−) abnormalities in the stated organ system or top-level HPO category. Fetuses with craniofacial abnormalities were significantly more likely to receive a molecular diagnosis than those without (p = 0.013). Significant p values (p < 0.05) are indicated by (*), Fisher’s exact test
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