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

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.

SUBMITTER: Normand EA

PROVIDER: S-EPMC6162951 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Normand Elizabeth A EA Braxton Alicia A Nassef Salma S Ward Patricia A PA Vetrini Francesco F He Weimin W Patel Vipulkumar V Qu Chunjing C Westerfield Lauren E LE Stover Samantha S Dharmadhikari Avinash V AV Muzny Donna M DM Gibbs Richard A RA Dai Hongzheng H Meng Linyan L Wang Xia X Xiao Rui R Liu Pengfei P Bi Weimin W Xia Fan F Walkiewicz Magdalena M Van den Veyver Ignatia B IB Eng Christine M CM Yang Yaping Y

Genome medicine 20180928 1

<h4>Background</h4>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.<h4>Methods</h4>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 d ...[more]

PMID: 30266093

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Project description:Background. Fetal malformations and other structural abnormalities are relatively frequent findings in the course of routine prenatal ultrasonographic examination. Due to their considerable genetic and clinical heterogeneity, the underlying genetic cause is often elusive and the resulting inability to provide a precise diagnosis precludes proper reproductive and fetal risk assessment. We report the development and first applications of an expanded exome sequencing-based test, coupled to a bioinformatics-driven prioritization algorithm, targeting gene disorders presenting with abnormal prenatal ultrasound findings. Methods. We applied the testing strategy to14 euploid fetuses, from 11 on-going pregnancies and three products of abortion, all with various abnormalities or malformations detected through prenatal ultrasound examination. Whole exome sequencing (WES) was followed by variant prioritization, utilizing a custom analysis pipeline (Fetalis algorithm), targeting 758 genes associated with genetic disorders which may present with abnormal fetal ultrasound findings. Results. A definitive or highly-likely diagnosis was made in 6 of 14 cases (43%), of which 3 were abortuses (Ellis-van Creveld syndrome, Ehlers-Danlos syndrome and Nemaline myopathy 2) and 3 involved on-going pregnancies (Citrullinemia, Noonan syndrome, PROKR2-related Kallmann syndrome). In the remaining eight on-going pregnancy cases (57%), a ZIC1 variant of unknown clinical significance was detected in one case, while in seven cases testing did not reveal any pathogenic variant(s). Pregnancies were followed-up to birth, resulting in one neonate harboring the PROKR2 mutation, presenting with isolated minor structural cardiac abnormalities, and in seven apparently healthy neonates. Discussion. The expanded targeted exome sequencing-based approach described herein (Fetalis), provides strong evidence suggesting a definite and beneficial increase in our diagnostic capabilities in prenatal diagnosis of otherwise chromosomally balanced fetuses with troubling ultrasound abnormalities. Furthermore, the proposed targeted exome sequencing strategy, designed primarily as a diagnostic rather than a research discovery tool, overcomes many of the problems and limitations associated with clinical wide-scale WES testing in a prenatal setting.

Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

Dataset Information

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

Publications

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

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