The 2019 International Conference on Prenatal Diagnosis and Therapy was held in Singapore 7-11 September. Dr Suzanne Drury, Clinical Genomics and Personalised Medicine Specialist at Congenica attended this year’s conference and writes about some of the key highlights amongst the many excellent presentations.

Carrier screening

The number of genes recommended for carrier screening has increased over the years, yet there is still debate about exactly which genes should be included in this testing. James Goldberg, Chief Medical Officer at Myriad Women’s Health presented on carrier screening in the era of expanding genetic technology.

Dr Goldberg highlighted several publications which have studied the number of diagnoses that would be made or missed by applying various frequencies and suggests that a carrier frequency of 1/100 in any population is a reasonable threshold on which to base inclusion on a screen.

The topic of carrier screening was also raised in the context of whether parents who are undergoing exome sequencing for diagnosis of their fetuses ultrasound anomaly should have their carrier status for returned for predefined conditions.

Part of an ongoing study by Dr Neeta Vora, University of North Carolina at Chapel Hill, is exploring this and it was also part of a wider, lively debate, which asked whether the 59 genes ACMG recommend reporting as secondary findings when sequencing postnatally should be reported when detected on fetal (and parental) sequencing.

Initially polling suggested the majority of the audience in favour (67%). It was argued that some results could be relevant in pregnancy, for example for an expectant mother found to have an RYR1 mutation associated with susceptibility to malignant hyperthermia, this would impact the choice of anaesthetic, which could avoid a severe and potentially fatal reaction to certain types of analgesic. However, after debate those in favour dropped to 54%. One of the arguments against, was that returning these secondary results is an unnecessary stress at a time when prospective parents already feel overwhelmed.

Exome sequencing for fetal diagnosis

A number of presentations focused on exome sequencing for fetuses with anomalies. Rhiannon Mellis, presenting data from the Prenatal Assessment of Genomes and Exomes (PAGE) study, looked in detail at whether fetuses with isolated increased nuchal translucency benefit from exome sequencing, and Antoni Borrell from the Hospital Clinic of Barcelona on the diagnostic rate using single gene, gene panel or exome sequencing for such fetuses.

Karen Stals, the 2018 Malcolm Fergusson Smith awardee presented her paper, where parental exome sequencing was used to diagnose cases of lethal or prenatal onset autosomal recessive disorders in the absence of the fetal sample. Using this approach, a diagnosis was made in 52% of cases.

Non-invasive prenatal diagnosis

Differing non-invasive methods of prenatal diagnosis for monogenic disease were presented at the event; Natalie Chandler and Joe Shaw presented on using cell-free DNA (cfDNA) circulating in maternal blood for targeted single gene disorders where there is a family history, whilst Liesbeth Vossaert showed data on isolating DNA from single circulating trophoblast (SCT) cells circulating in maternal blood from early gestation and twin pregnancies, using whole genome amplification and sequencing.
Both methods had differing benefits - SCT has a benefit over cfDNA as the DNA is not fragmented and just relates to the fetus, whereas cfDNA contains both maternal and fetal DNA, but there is a paucity of circulating cells in SCT, and these also need to be sorted, to select those which are from the trophoblast.

Therapy and treatment

Genetic diagnosis is leading to development of personalized treatment and this was exemplified by various presentations showing how far this field is moving. Tippi Mackenzie from the University of California, San Francisco presented a phase I clinical trial on in utero HSC transplantation for alpha thalassemia major, and William Peranteau from the Children’s Hospital of Philadelphia (CHOP) described studies using in utero gene editing for surfactant protein deficiency which causes lung failure after birth.

Congenica presents new prenatal data

It was a varied and exciting meeting, with the role of genomics in this space very apparent. Congenica was also excited to share initial results from its newly developed, non-invasive test for detection of disease-causing variants associated with fetal anomalies which arise de novo, with initial results showing 100% clinical sensitivity. Congenica also presented the results of a single-center study using exome sequencing for the diagnosis of fetal structural anomalies, with a diagnostic yield of 40%.

Rapidly identify the cause of prenatal fetal anomalies

Prenatal genetic diagnosis is a critical but complex clinical challenge to inform decisions during pregnancy and after birth. To support the analysis of ultrasound-detected fetal anomalies faster than ever before, we have developed Congenica Prenatal, a pre-configured application available within our clinical decision support platform, with expert curated and annotated gene panels, enabling you to rapidly identify the molecular cause of fetal anomalies.

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