Evaluation of Rapid First-line Genome Sequencing for Prenatal Diagnosis of Congenital Malformations in Comparison With Chromosomal Microarray and Exome Sequencing

The management of congenital malformations (3% of pregnancies) by prenatal ultrasound represents a real medical challenge. Their prognosis is variable depending on the underlying aetiology. In France, prenatal diagnosis (PND) has long been based on imaging or infectious, metabolic, immunological or genetic investigations (karyotype, chromosomal microarray (CMA) and sequencing of targeted genes in some cases). About 70% of foetuses remain without an etiological diagnosis after these investigations. Exome (ES) and genome sequencing (GS) has revolutionized medical genetics, with a postnatal diagnostic rate of more than 40% for developmental disorders in the absence of clinical orientation and/or after a negative standard workup. In PND, trio-ES has been progressively introduced in several countries in a diagnostic approach to refine the prognosis and help couples to make decisions regarding the current pregnancy, but also for the subsequent family planning/counselling. However, the delay in the return of results, 3 to 4 weeks on average, is long for couples. Also, ES cannot detect some variants, like structural variants, accessible to GS, that may lead to additional diagnosis in 5 to 10% of cases.

Since 2013, the FHU TRANSLAD has been transferring ES in diagnosis for patients with rare diseases with developmental anomalies, by deploying different pilot projects. In PND, our team was the first in France to propose a national research project, AnDDI-Prenatome, supported by the AnDDI-Rares health network, to evaluate the feasibility of analyzing ES and delivering results in less than 4 weeks in the context of congenital malformations (PMID:37035737). The teams were able to demonstrate the feasibility of prenatal ES implementation, with on overall diagnostic yield of 41% (37/89) when ES was used as a first-line test and 31% (19/61) when used after a normal CMA. This experience has enabled the implementation of ES in routine diagnosis, with an offer for the French hospitals. Our team now coordinates the DPNI-Exome trial (interregional PHRC; NCT05182242), comparing non-invasive and invasive approaches for fetal ES in PND when foetal ultrasound signs are discovered.

Our team now wishes to evaluate the diagnostic yield and the percentage of results delivery in less than 7 days of rapid trio-GS in case of ultrasound signs, to reduce the delay of results, but also possibly increase the rate of PND. In addition, information concerning the efficiency of rapid trio-GS as well as technical hurdles associated with its implementation will permit the development of national guidelines.

This is a question of outmost importance from an international scientific point of view because currently only six publications have proposed the use of the rapid prenatal GS, while around seventy studies report an experience of prenatal ES. Five of these six publications were from China, sometimes retrospective, with no or limited information regarding the methods, inclusion criteria, delays, nor difficulties encountered, and often a low number of included patients. The efficiency cannot be deducted from these publications. The proposed study should answer if rapid trio-GS could be implemented in routine PND in France.

The team is committed to assessing the impact of new reproductive technologies on couples. It has already carried out longitudinal qualitative studies, in the DPNI-Exome study, which showed the difficulties couples face when waiting for different results, delivered in different timeframes. GS makes it possible to offer only one unique test, which could answer the parents' questions. The team do their best to ensure that the results are delivered very quickly, but the psychologists mentioned that waiting for the results gives the couple sufficient time to realise the discovery of ultrasound signs, and the possible impact on the pregnancy prognosis. It is therefore important to assess couples' perceptions and satisfaction with a single test, which is quicker than what is offered in the standard care, and to evaluate whether the time needed to obtain the results is sufficient for their decision-making. This could be assessed by semi-directive interviews.