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

Elizabeth Quinlan-Jones, Jenny Lord, Denise Williams, Sue Hamilton, Tamas Marton, Ruth Y Eberhardt, Gabriele Rinck, Elena Prigmore, Rebecca Keelagher, Dominic J McMullan, Eamonn R Maher, Matthew E Hurles, Mark D Kilby

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1065-1073
Number of pages9
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number5
Early online date8 Oct 2018
Publication statusPublished - May 2019


  • Autopsy/methods
  • Cohort Studies
  • Congenital Abnormalities/diagnosis
  • Exome/genetics
  • Female
  • Fetal Diseases/diagnosis
  • Fetus/diagnostic imaging
  • Humans
  • Infant, Newborn
  • Male
  • Pregnancy
  • Prenatal Diagnosis/methods
  • Exome Sequencing/methods


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