Journal
GENETICS IN MEDICINE
Volume 21, Issue 5, Pages 1065-1073Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-018-0298-8
Keywords
exome sequencing; fetuses; neonates; autopsy; genetic diagnosis
Categories
Funding
- Health Innovation Challenge Fund [HICF-R7-396]
- Department of Health
- Wellcome Trust
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- NIHR Senior Investigator Award
- PAGE Study [HICF-R7-396]
- Wellcome Sanger Institute, Hinxton, Cambridge, UK
- West Midlands Fetal Medicine Centre, Birmingham Women's & Children's NHS Foundation Trust, Birmingham, UK
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- UCL Great Ormond Street Institute of Child Health
- North East Thames Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK
- Department of Medical Genetics, University of Cambridge
- NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK
- UCL Great Ormond Street Institute of Child Health and North East Thames Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK
- ARC, London, UK
- Wellcome Centre for Ethics and Humanities
- Ethox Centre, University of Oxford, UK
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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.
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