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Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.
Genet Med. 2019 05; 21(5):1065-1073.GM

Abstract

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.

Authors+Show Affiliations

Department of Clinical Genetics, Birmingham Women's & Children's NHS Foundation Trust, Birmingham, UK. West Midlands Fetal Medicine Centre, Birmingham Women's & Children's NHS Foundation Trust, Birmingham, UK.Wellcome Sanger Institute, Hinxton, Cambridge, UK.Department of Clinical Genetics, Birmingham Women's & Children's NHS Foundation Trust, Birmingham, UK.West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.West Midlands Regional Perinatal Pathology Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.Wellcome Sanger Institute, Hinxton, Cambridge, UK.Wellcome Sanger Institute, Hinxton, Cambridge, UK.Wellcome Sanger Institute, Hinxton, Cambridge, UK.West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.Wellcome Sanger Institute, Hinxton, Cambridge, UK.West Midlands Fetal Medicine Centre, Birmingham Women's & Children's NHS Foundation Trust, Birmingham, UK. M.D.Kilby@bham.ac.uk. Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. M.D.Kilby@bham.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30293990

Citation

Quinlan-Jones, Elizabeth, et al. "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, vol. 21, no. 5, 2019, pp. 1065-1073.
Quinlan-Jones E, Lord J, Williams D, et al. Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. Genet Med. 2019;21(5):1065-1073.
Quinlan-Jones, E., Lord, J., Williams, D., Hamilton, S., Marton, T., Eberhardt, R. Y., Rinck, G., Prigmore, E., Keelagher, R., McMullan, D. J., Maher, E. R., Hurles, M. E., & Kilby, M. D. (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
Quinlan-Jones E, et al. Molecular Autopsy By Trio Exome Sequencing (ES) and Postmortem Examination in Fetuses and Neonates With Prenatally Identified Structural Anomalies. Genet Med. 2019;21(5):1065-1073. PubMed PMID: 30293990.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. AU - Quinlan-Jones,Elizabeth, AU - Lord,Jenny, AU - Williams,Denise, AU - Hamilton,Sue, AU - Marton,Tamas, AU - Eberhardt,Ruth Y, AU - Rinck,Gabriele, AU - Prigmore,Elena, AU - Keelagher,Rebecca, AU - McMullan,Dominic J, AU - Maher,Eamonn R, AU - Hurles,Matthew E, AU - Kilby,Mark D, Y1 - 2018/10/08/ PY - 2018/04/10/received PY - 2018/08/29/accepted PY - 2018/10/9/pubmed PY - 2020/2/14/medline PY - 2018/10/9/entrez KW - autopsy KW - exome sequencing KW - fetuses KW - genetic diagnosis KW - neonates SP - 1065 EP - 1073 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 21 IS - 5 N2 - 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/30293990/Molecular_autopsy_by_trio_exome_sequencing__ES__and_postmortem_examination_in_fetuses_and_neonates_with_prenatally_identified_structural_anomalies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1098-3600(21)01474-X DB - PRIME DP - Unbound Medicine ER -