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

Research output: Contribution to journalArticlepeer-review


  • Elizabeth Quinlan-jones
  • Jenny Lord
  • Denise Williams
  • Sue Hamilton
  • Tamas Marton
  • Ruth Y. Eberhardt
  • Gabriele Rinck
  • Elena Prigmore
  • Rebecca Keelagher
  • Dominic J. Mcmullan
  • Matthew E. Hurles


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. KMT2Dvariants (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
Number of pages9
JournalGenetics in Medicine
Early online date8 Oct 2018
Publication statusE-pub ahead of print - 8 Oct 2018


  • exome sequencing, fetuses, neonates, autopsy, genetic diagnosis