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Importance of complete phenotyping in prenatal whole exome sequencing.
Hum Genet. 2018 Feb; 137(2):175-181.HG

Abstract

Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects. Re-analysis of WES variants and combination of prenatal and postnatal phenotyping yielded pathogenic variants in at least 20% of cases including PORCN gene in a fetus with split-hand/foot malformation, as well as variants of uncertain significance in NEB and NOTCH1 in fetuses with postnatal muscle weakness and Adams-Oliver syndrome, respectively. Furthermore, Sanger sequencing in a patient with holoprosencephaly, elucidated by postnatal MRI, revealed a pathogenic 47-base pairs deletion in ZIC2 which was missed by prenatal WES. This study suggests that incomplete prenatal phenotyping and lack of prenatal ultrasound-genotype databases are the limiting factors for current interpretation of WES data in prenatal diagnosis. Development of prenatal phenotype-genotype databases would significantly help WES interpretation in this setting. Patients who underwent prenatal clinical WES may benefit from the re-analysis based on detailed postnatal findings.

Authors+Show Affiliations

Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Westminster College, New Wilmington, PA, USA. Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA.Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA.Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA. rajkovica2@mail.magee.edu. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. rajkovica2@mail.magee.edu. Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. rajkovica2@mail.magee.edu. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. rajkovica2@mail.magee.edu. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. rajkovica2@mail.magee.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29392406

Citation

Aarabi, Mahmoud, et al. "Importance of Complete Phenotyping in Prenatal Whole Exome Sequencing." Human Genetics, vol. 137, no. 2, 2018, pp. 175-181.
Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137(2):175-181.
Aarabi, M., Sniezek, O., Jiang, H., Saller, D. N., Bellissimo, D., Yatsenko, S. A., & Rajkovic, A. (2018). Importance of complete phenotyping in prenatal whole exome sequencing. Human Genetics, 137(2), 175-181. https://doi.org/10.1007/s00439-017-1860-1
Aarabi M, et al. Importance of Complete Phenotyping in Prenatal Whole Exome Sequencing. Hum Genet. 2018;137(2):175-181. PubMed PMID: 29392406.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Importance of complete phenotyping in prenatal whole exome sequencing. AU - Aarabi,Mahmoud, AU - Sniezek,Olivia, AU - Jiang,Huaiyang, AU - Saller,Devereux N, AU - Bellissimo,Daniel, AU - Yatsenko,Svetlana A, AU - Rajkovic,Aleksandar, Y1 - 2018/02/01/ PY - 2017/09/24/received PY - 2017/12/16/accepted PY - 2018/2/3/pubmed PY - 2019/3/27/medline PY - 2018/2/3/entrez SP - 175 EP - 181 JF - Human genetics JO - Hum Genet VL - 137 IS - 2 N2 - Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects. Re-analysis of WES variants and combination of prenatal and postnatal phenotyping yielded pathogenic variants in at least 20% of cases including PORCN gene in a fetus with split-hand/foot malformation, as well as variants of uncertain significance in NEB and NOTCH1 in fetuses with postnatal muscle weakness and Adams-Oliver syndrome, respectively. Furthermore, Sanger sequencing in a patient with holoprosencephaly, elucidated by postnatal MRI, revealed a pathogenic 47-base pairs deletion in ZIC2 which was missed by prenatal WES. This study suggests that incomplete prenatal phenotyping and lack of prenatal ultrasound-genotype databases are the limiting factors for current interpretation of WES data in prenatal diagnosis. Development of prenatal phenotype-genotype databases would significantly help WES interpretation in this setting. Patients who underwent prenatal clinical WES may benefit from the re-analysis based on detailed postnatal findings. SN - 1432-1203 UR - https://www.unboundmedicine.com/medline/citation/29392406/Importance_of_complete_phenotyping_in_prenatal_whole_exome_sequencing_ L2 - https://dx.doi.org/10.1007/s00439-017-1860-1 DB - PRIME DP - Unbound Medicine ER -