Thuong Ha^1,2,3, Genomic Autopsy Study Research Network, *Christopher Barnett^3,4,5, *Hamish Scott^1,2,3,6,7

¹Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia; ²Centre of Cancer Biology, alliance between SA Pathology and UniSA, Adelaide, Australia; ³Adelaide Medical School, University of Adelaide, Adelaide, Australia; ⁴Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, Australia; ⁵Australian Genomics, Melbourne, Australia; ⁶ACRF Cancer Genomics Facility, SA Pathology, Adelaide, Australia, Australia; ⁷Clinical and Health Sciences Unit, University of South Australia, Adelaide, Australia

In Australia, 6 babies are stillborn and 2 die within 28 days of life. Using genomic autopsy as an adjunct for standard autopsy, a definitive diagnosis can be established in 20% of families with pregnancy loss and perinatal death, while another 20% had a candidate diagnosis requiring further investigations. From a study cohort of >400 families, 60% of families remain unresolved following clinical exome (ES) and genome (GS) analysis.

Using a systematic translational framework, we aim to increase the number of candidate and definitive diagnosis in families with negative ES and GS clinical findings. For consented families, genotype and phenotype data were shared with national and international programs for periodic reanalysis. All candidate variants and genes of uncertain significance were genematched. For cases with clinically accessible tissues, RNA and methylation studies were performed for the detection of aberrant splicing and episignatures. Mouse models for novel (potentially lethal) autosomal recessive disorders were established.

Periodic analysis of existing genomic data, with an adjunct functional framework, has provided genetic and experimental evidence for novel disease-gene associations, and variant reclassifications, facilitating clinical prenatal testing. 

*NB: Scott and Barnett are senior coauthors.