First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects
- Published
- Accepted
- Subject Areas
- Genetics, Genomics, Medical Genetics
- Keywords
- exome sequencing, fetal malformations, prenatal diagnosis, gene disorders
- Copyright
- © 2016 Pangalos et al.
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ Preprints) and either DOI or URL of the article must be cited.
- Cite this article
- 2016. First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects. PeerJ Preprints 4:e1811v1 https://doi.org/10.7287/peerj.preprints.1811v1
Abstract
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 3 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 8 on-going pregnancy cases (57%), a ZIC1 variant of unknown clinical significance was detected in one case, while in 7 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 7 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.
Author Comment
The exciting work presented in this paper, highlights interesting developments regarding a new exome sequencing testing strategy - Fetalis - designed for uncovering pathogenic gene mutations in fetuses with troubling ultrasound abnormalities. This article has been submitted to PeerJ for review.
Supplemental Information
NGS coverage analysis metrics
Whole exome sequencing coverage analysis metrics for each case.