Milan, Italy: Pregnancy loss and the death of a new-born baby are devastating events, and as of today around 25% of these perinatal deaths are unexplained despite autopsy. Discovering the cause of such a loss is of great importance for the bereaved parents, both in providing an explanation and in helping them to understand the likelihood of a recurrence in future pregnancies. Researchers in Australia have used state-of-the-art genetic testing in order to help provide answers in such cases.
Associate Professor Christopher Barnett, a clinical geneticist who is Head of the Paediatric and Reproductive Genetics Unit at the Women’s and Children’s Hospital, North Adelaide, told the European Society of Human Genetics conference how he and colleagues are using whole exome sequencing (WES)  and whole genome sequencing (WGS)  to detect causes of neonatal death in cases where this has so far remained unidentified. Using data from 43 families referred to the genetics unit, where samples were available from both parents and the fœtus (the prospective cohort), and 60 from stored autopsy samples from the fœtus or new-born (the retrospective cohort), the researchers were able to uncover an underlying genetic cause in 23% of the prospective cohort and have found a single promising candidate in a further 26%.
Solved cases included new disease gene discoveries, new syndrome identification and novel severe fœtal presentations of existing rare paediatric disease. In the retrospective cohort, strong candidates for the cause of death were found in 18% of cases.
“This study has contributed directly to the birth of healthy babies,” Prof Barnett told the conference. “We have had numerous couples who, with successful preimplantation genetic diagnosis via in vitro fertilisation in subsequent pregnancies, or through prenatal testing during pregnancy, have been able to avoid the genetic condition experienced in a prior pregnancy. Of course, this can only be offered to couples if a definitive genetic diagnosis is made in the earlier affected pregnancy, and this is the primary aim of our study. These conditions are often extremely rare and, indeed, in some cases they are totally new.”
According to the World Health Organisation, in 2009 there were 2.6 million stillbirths (the death of the fœtus at or after 22 weeks of pregnancy) across the world, with more than 8200 deaths per day. Among the 133 million babies born alive each year, 2.8 million die in the first week of life.
In Australia, a standard perinatal autopsy is done in about 60% of cases of unexplained fœtal or neonatal death and termination of pregnancy for congenital abnormalities. Some genetic testing is done, but it is limited, usually to chromosomal analysis. As in most other countries, specific genetic sequencing is not a standard part of the autopsy process and when it does occur it is generally limited to a particular condition or a relatively short list of genes. “We are offering the testing of all human genes so that we can increase the rate of diagnosis as much as possible,” says Prof Barnett.
One of the main ethical features of the study is that it involves testing the parents as well as the fœtus/new-born. This means that the consent procedure needs to be rigorous and occur in a face-to-face setting with the clinical geneticist at the time of the counselling that is provided for follow-up of the first autopsy. The genetic diagnoses of the parents may have the potential to affect their health later in life, and the consent process allows them to opt out from knowing these results if they so wish.
“Our results provide new insights into the molecular mechanisms of early development. We are not surprised that a significant proportion of ‘unexplained’ fœtal and new-born deaths and congenital abnormalities have an underlying genetic cause, and we believe that genomic autopsy should be used routinely in the investigation of pregnancy loss and perinatal death,” Prof Barnett concluded.
Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, UK, said: “It is often unclear what the cause is of pregnancy loss or the death of a new-born baby. This work shows how state-of-the-art genomic testing can be used as part of the routine autopsy procedure to reveal a genetic cause in up to a quarter of all neonatal cases. A genetic diagnosis can be used to prevent complications in future pregnancies and provide much needed answers to the families involved.”
 Whole exome sequencing is a technique for sequencing all the genes in a genome that code for proteins. Because disease-causing genes are much more likely to be found in the protein-coding sequence, focusing on this limited area costs much less than whole genome sequencing but is still able to provide a high yield of results.
 Whole genome sequencing is the process of determining the complete DNA sequence of an individual, including all the chromosomal DNA and that contained in the mitochondria.
Abstract no: C15.5. The Genomic Autopsy Study: using genomics as an adjunct to standard autopsy to unlock the cause of complex fetal and neonatal presentations
The research was funded by the Australian National Health and Medical Research Council (NHMRC), and sequencing support provided by the Broad Institute in Boston, USA.