Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.
McMullan, Dominic J
Hurles, Matthew E
Genetics in medicine : official journal of the American College of Medical Genetics
Wolters Kluwer Health
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Quinlan-Jones, E., Lord, J., Williams, D., Hamilton, S., Marton, T., Eberhardt, R. Y., Rinck, G., et al. (2019). Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.. Genetics in medicine : official journal of the American College of Medical Genetics, 21 (5), 1065-1073. https://doi.org/10.1038/s41436-018-0298-8
Purpose: To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal or early infant death. Methods: ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using ACMG guidelines. Results: A genetic diagnosis was established in 10 cases (37%). Pathogenic/likely pathogenic variants were identified in 9 different genes including 4 de novo autosomal dominant, 3 homozygous autosomal recessive, 2 compound heterozygous autosomal recessive and 1 X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in 2 cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1) or abdominal abnormalities (1). Conclusion: This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.
Fetus, Humans, Fetal Diseases, Prenatal Diagnosis, Autopsy, Cohort Studies, Pregnancy, Infant, Newborn, Female, Male, Congenital Abnormalities, Exome, Whole Exome Sequencing
This publication is part of the PAGE Study and represents independent research commissioned by the Health Innovation Challenge Fund (HICF‐R7‐396), a parallel funding partnership between the Department of Health and Wellcome Trust. The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health or Wellcome Trust. EM acknowledges support from NIHR Cambridge Biomedical Research Centre and a NIHR Senior Investigator Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve.
Wellcome Trust Sanger Institute, Genome Research Limited (PAGE project code S4029)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10035)
External DOI: https://doi.org/10.1038/s41436-018-0298-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285467
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/