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

Abstract

BackgroundExome 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.MethodsWe 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.ResultsPrenatal 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.ConclusionExome 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.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0582-x) contains supplementary material, which is available to authorized users.

Accuracy of in-utero MRI to detect fetal brain abnormalities and prognosticate developmental outcome: postnatal follow-up of the MERIDIAN cohort

“…The challenges of delivering exome studies in a timely manner in antenatal care also need to be overcome, along with explaining to families the problem of phenotypical variation between individuals with the same mutation, even within a single family. 41,42 Project three looked at children who had IMVM. Most children with this antenatal diagnosis do not show adverse developmental outcomes, so fetal maternal clinicians usually give a favourable prognostic category.…”

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

“…The disadvantages are that panel content may not be up to date with the newest disease gene discoveries because they are typically developed on the basis of information on disease genes for conditions that present after birth and not optimized for prenatal presentations. A potentially more successful strategy that we favor is genome‐wide sequencing, such as diagnostic exome sequencing, which has already shown benefit for prenatal cases with CNS abnormalities, but full investigation of the clinical utility and their place in prenatal genetic testing is still underway …”

Prenatal Diagnosis of Fetuses with Increased Nuchal Translucency by Genome Sequencing Analysis

“…Owing to the breakthrough of molecular technologies such as next-generation sequencing and its reduction of costs over the years, whole-exome sequencing (or exome sequencing, WES) has been applied for both research purposes and clinical use (Drury et al, 2015;Fu et al, 2018;Leung et al, 2018;Normand et al, 2018;Lord et al, 2019;Petrovski et al, 2019). Emerging studies show WES has the ability to provide genetic diagnoses ranging from 9.1% to 32% for the fetuses with a structural anomaly (Drury et al, 2015;Fu et al, 2018;Leung et al, 2018;Normand et al, 2018;Lord et al, 2019;Petrovski et al, 2019), while among these cases, WES yielded diagnoses in 3.2% to 21% of the fetuses with increased NT with/without structural malformations (Drury et al, 2015;Lord et al, 2019;Petrovski et al, 2019). However, most of these studies were conducted on prenatal cohorts after the exclusion of abnormal karyotypes and/or CMA results attributed to the cost and the limited ability of WES in CNV detection (Belkadi et al, 2015).…”