Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

Kathleen A. Drexler; Asha N. Talati; Kelly L. Gilmore; Rachel V. Veazey; Bradford C. Powell; Karen E. Weck; Erica E. Davis; Neeta L. Vora

doi:10.1016/j.gim.2023.100915

Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

Kathleen A. Drexler^*, Asha N. Talati, Kelly L. Gilmore, Rachel V. Veazey, Bradford C. Powell, Karen E. Weck, Erica E. Davis, Neeta L. Vora

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping. Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs. Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01). Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results.

Original language	English (US)
Article number	100915
Journal	Genetics in Medicine
Volume	25
Issue number	10
DOIs	https://doi.org/10.1016/j.gim.2023.100915
State	Published - Oct 2023

Funding

Funding for this research was supported by the following grants:, R21 TR002770 (National Center for Advancing Translational Sciences: PIs: Vora; Davis), R01 HD105868 (National Institute for Child and Human Development; PI; Vora), Additional funding sources:, NICHD R01HD105868 (PI: Vora); NICHD K23HD088742 (PI: Vora); NICHD: K12HD00144116 (PI: Boggess); NCATS R21TR002770 (PI: Vora). Conceptualization: N.L.V. A.N.T. K.L.G. K.A.D.; Data Curation: N.L.V. A.N.T. K.L.G. K.A.D.; Formal Analysis: N.L.V. A.N.T. K.L.G. K.A.D.; Funding Acquisition: N.L.V. E.E.D.; Investigation: N.L.V. A.N.T. K.L.G. K.A.D. E.E.D. R.V.V. B.C.P. K.E.W.; Methodology: N.L.V. A.N.T. K.L.G. E.E.D.; Project Administration: N.L.V. K.L.G. E.E.D.; Resources: N.L.V. K.L.G. K.E.W. B.C.P.; Writing-original draft: N.L.V. A.N.T. K.L.G. K.A.D. E.E.D. R.V.V. B.C.P. K.E.W.; Writing-review and editing: K.A.D. N.L.V. A.N.T. K.L.G. E.E.D. This study was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill (IRB 13-4084). Informed consent was obtained from all participants before enrollment. All reported and stored individual data were de-identified.

Keywords

Congenital anomalies
Deep phenotyping
Exome sequencing
Fetal brain anomalies
Prenatal diagnosis

ASJC Scopus subject areas

Genetics(clinical)

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Cite this

@article{10e5be61797f4600a682268298fbf745,

title = "Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities",

abstract = "Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping. Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs. Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01). Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results.",

keywords = "Congenital anomalies, Deep phenotyping, Exome sequencing, Fetal brain anomalies, Prenatal diagnosis",

author = "Drexler, {Kathleen A.} and Talati, {Asha N.} and Gilmore, {Kelly L.} and Veazey, {Rachel V.} and Powell, {Bradford C.} and Weck, {Karen E.} and Davis, {Erica E.} and Vora, {Neeta L.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = oct,

doi = "10.1016/j.gim.2023.100915",

language = "English (US)",

volume = "25",

journal = "Genetics in Medicine",

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T1 - Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

AU - Drexler, Kathleen A.

AU - Talati, Asha N.

AU - Gilmore, Kelly L.

AU - Veazey, Rachel V.

AU - Powell, Bradford C.

AU - Weck, Karen E.

AU - Davis, Erica E.

AU - Vora, Neeta L.

PY - 2023/10

Y1 - 2023/10

N2 - Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping. Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs. Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01). Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results.

AB - Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping. Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs. Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01). Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results.

KW - Congenital anomalies

KW - Deep phenotyping

KW - Exome sequencing

KW - Fetal brain anomalies

KW - Prenatal diagnosis

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Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

Abstract

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