TY - JOUR
T1 - Exome sequencing for perinatal phenotypes
T2 - The significance of deep phenotyping
AU - Aggarwal, Shagun
AU - Vineeth, Venugopal Satidevi
AU - Das Bhowmik, Aneek
AU - Tandon, Ashwani
AU - Kulkarni, Aditya
AU - Narayanan, Dhanya Lakshmi
AU - Bhattacherjee, Amrita
AU - Dalal, Ashwin
N1 - Funding Information:
Authors are thankful to the families for participation in the study. We would like to acknowledge Medgenome Labs, Bangalore, India and Centogene Labs, Germany for performing the exome sequencing wet lab experiments.
Funding Information:
This work has been done using research grant provided by Science and Engineering Research Board (SERB), Government of India (file no. EMR/2016/002478).
Publisher Copyright:
© 2019 John Wiley & Sons, Ltd.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Objective: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. Methods: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype–based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. Results: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Conclusion: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.
AB - Objective: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. Methods: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype–based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. Results: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Conclusion: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.
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U2 - 10.1002/pd.5616
DO - 10.1002/pd.5616
M3 - Article
C2 - 31742715
AN - SCOPUS:85076147782
SN - 0197-3851
VL - 40
SP - 260
EP - 273
JO - Prenatal Diagnosis
JF - Prenatal Diagnosis
IS - 2
ER -