Although whole genome sequencing is currently used for diagnostics in various countries, and France has just launched the France Genomic Medicine Plan 2025 (PFMG2025)[1], its use in neonatal emergency care is still not widespread. However, the speed at which a genetic examination can be performed is crucial when an emergency diagnosis is needed. This is a common situation for rare pediatric diseases with an early onset or rapid progression. The teams at CHU Dijon-Bourgogne, Inserm and the CEA have conducted a pilot study of the feasibility of emergency high-throughput genome sequencing prior to consideration of the process in the future as part of PFMG2025.
As part of this pilot study, Fastgenomics[2], emergency genome analyses have been carried out in the last nine months for approximately thirty babies with rare developmental disorders (AnDDI-rares[3]) in neonatal intensive care at eight French hospitals. The high-throughput genome sequencing of the children and their parents and a primary bioinformatics analysis were carried out on the sequence production platform at France's national human genomics research center (CEA-CNRGH), in collaboration with the CEA's supercomputing center (TGCC) and the University of Burgundy's computing center (CCuB). The genomic data were interpreted by FHU TRANSLAD in close collaboration with the Inserm U1231 GAD research team.
The mobilization of these teams enabled the analysis results to be delivered in 49 days, or as quickly as 38 days in some cases. This is particularly fast for genetic diagnostics. Despite significant improvements, the average time taken to obtain a genetic diagnosis in France is still very long: 1.5 years on average and up to 5 years for 25% of patients. Fast genome analysis of these newborns produced a diagnosis for two thirds of them, and a third benefited from faster, more appropriate treatment.
These fast genome analyses were possible because of major advances in the high-throughput sequencing of the whole genome. New generation high-throughput DNA sequencing technologies, which can be used to study a person's whole genome, have emerged in the last few years as a tool of choice for studying rare diseases. These cutting-edge technologies are used at the CNRGH and have already identified the involvement of numerous genes in many diseases. The FHU TRANSLAD team at CHU Dijon-Bourgogne was one of the first in France to demonstrate the value of exome sequencing (the exome represents 1% of the whole genome) in the diagnosis of severe early-onset pediatric pathologies and developmental and intellectual disability disorders.
Diagnosis of rare diseases in newborns
Rare diseases (affecting less than one person in every 2,000) are a major public health challenge because there are approximately 8,000 of them and they affect more than 3 million people in France. In most cases onset occurs during childhood, and they are responsible for 10% of deaths before the age of 5 years. Up to 80 of these diseases are genetic in origin. Obtaining a diagnosis has many benefits for patients and their families: clarification of the cause, a more accurate prognosis, access to treatment or to clinical trials, knowledge of the risks of recurrence, avoidance of duplication with many other diagnostic tests, prevention of known future complications, easier access to special assistance for families, and in some cases contact with other families suffering from the same disease.
Obtaining a diagnosis is a major challenge for pediatric diseases with an early onset and rapid progression, which can have very diverse genetic causes, such as epilepsy, metabolic disorders, heart defects, musculoskeletal disorders and other polymalformative syndromes. The 3rd Rare Diseases Plan (PNMR3) aims to ensure everyone has an accurate diagnosis within one year because diagnostic delay results in "a potential worsening of the patient's condition, delayed access to genetic counseling options and the wasting of medical resources (multiplicity of diagnostic consultations)".
Obtaining a rapid diagnosis is even more important for serious illnesses in newborn babies. An accurate diagnosis can lead to changes in the way a baby is cared for, through provision of more suitable treatments (e.g. in cases of metabolic disorders or epilepsy), referral to a specialist in the disorder, dietary changes, further examinations and/or a review of the need for surgery; the result can also be taken into account in discussions as to whether treatment should continue.
[1] In 2016, France launched the France Genomic Medicine Plan 2025 (PFMG2025). It aims to roll out genome sequencing for the diagnosis of rare diseases by setting up ultra-high-throughput sequencing platforms to perform whole genome sequencing on a large scale and by running pilot studies to define rules for prescribing these analyses.
[2] Fastgenomics: National pilot study developed by the specialist national healthcare organization AnDDI-rares, FHU TRANSLAD and CEA-CNRGH and supported by a financial donation from the SANOFI-GENZYME laboratory.
[3] AnDDI-rares: A national rare diseases healthcare organization specifically for somatic and cognitive developmental disorders. http://anddi-rares.org