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Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.

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Quinlan-Jones, Elizabeth 
Lord, Jenny 
Williams, Denise 
Hamilton, Sue 
Marton, Tamas 


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 American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two 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 (1) abnormalities. 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.



autopsy, exome sequencing, fetuses, genetic diagnosis, neonates, Autopsy, Cohort Studies, Congenital Abnormalities, Exome, Female, Fetal Diseases, Fetus, Humans, Infant, Newborn, Male, Pregnancy, Prenatal Diagnosis, Exome Sequencing

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Genet Med

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Elsevier BV
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)
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.