Parents with children with diseases that are difficult to diagnose because they are rare or unknown “always ask three questions: what’s wrong with my child? Can he be treated? And what will his future be? To answer these questions, you need to have a diagnosis. the use of all the techniques available to give diagnoses to families in certain times is fundamental” because “the cost of a diagnostic delay is appalling not only for an economic issue but also in terms of emotional impact for the family. to all families a clear contract indicating what you do, with what prospects and when. Informed consent cannot fail to have this information “. So Andrea Bartuli, head of the Rare Diseases and Medical Genetics Unit, Bambino Gesù Pediatric Hospital in Rome, speaking today at the digital conference ‘Towards a national plan for precision medicine: rare diseases laboratory of omics sciences’.
The conference is organized by Omar (Observatory for rare diseases), Bambino Gesù pediatric hospital and Orphanet Italia, with the patronage of the Italian Society of Bioinformatics (Bits), the Hopen Onlus Foundation, Sibioc (Italian Society of Clinical Biochemistry and Clinical Molecular Biology – Medicine of laboratory) and with the unconditional contribution of JuliaOmix™ from GenomeUp, Roche Diagnostics and Thermo Fisher Scientific. The parents come from “an odyssey. If the families have been around for a long time – continues Bartuli – it means that the genetic problem involved is not very clear. When the conditions have an evident clinical trend that allows us to immediately highlight the genes involved, one can do genomic research, but when there is no clear diagnostic hypothesis or when the diagnostic hypothesis is not confirmed, exome analysis must be done (Wes)”.
Next generation sequencing (NGS) techniques include a number of complementary approaches: exome analysis (WES), which analyzes the coding part of the genome; genome sequencing (Wgs), which also analyzes non-coding regions; transcriptome (Ts) analysis, which identifies events that impact gene expression in quantitative and qualitative terms; the analysis of the methylome, which allows to functionally validate the genomic variants of uncertain significance. The West, to a lesser extent, the Wgs have entered the clinical practice of numerous countries, above all to support the diagnosis of rare patients and the stratification of patients suffering from oncological diseases.
“If there is no clear hypothesis – underlines Bartuli – we need exome analysis and we need competent laboratories, with experience and a large amount of activity because they are techniques that have now collapsed in terms of costs, but which to be sustainable must be in centers of diagnostic capacity. In a multi-regional national system like ours, it is unthinkable that there is a center of this kind in every region. For rare diseases there must be a national project that goes beyond the regional logic, as for tumors or transplants”. In this regard, “the intervention of the Human Genomics Society at the tables of the ministry – observes the expert – and a map drawn together that defines these aspects is essential to give dignity to conditions that determine a low quality of life in children and a frightening social impact in families and also to contain costs at a national level. It is necessary to avoid repeating surveys with a waste of time and money, when an exomic survey that can give answers is enough”.
Not all mutations are known. “In research and diagnostics we have a continuous sequencing of small patients who have immunodeficiency diseases”, adds, in his speech, Dejan Lazarevic, Coordinator of the Genomics lab, Omics Sciences, Irccs San Raffaele Hospital in Milan. “The discovery of the mutations in these patients – he continues – allows the application of gene therapy which could resolve the issue. Sequencing is fine when you are looking for a known mutation, but when there are unknown mutations you have to go through a series of evaluations that require a major effort from basic research to demonstrate that the variant is indeed the cause of the pathology”.
Ngs techniques, whose costs and times have been reduced by over 200 thousand times in the last 20 years, have proven to be useful not only in diagnosis, but also to benefit from targeted treatments and precision therapies on molecular targets. The cost-effectiveness evidence in rare disease patients justify its use as a first choice test in patients without diagnosis. Wes solves 30 to 60 percent of the problem of undiagnosed patients. The Italian commitment to genomics is based on the 2013 ‘Guidelines for genomics in public health’ and on the 2018 ‘Plan for the innovation of the health system based on omics sciences’. In 2020, a document from the working group of Section I of the Higher Health Council (CSS). Among the recommendations are: the inclusion in the Essential Levels of Assistance (Lea) of Wes sequencing as a first choice investigation or as a diagnostic study, especially in rare diseases, oncological diseases and in the study of the microbiome; the creation of a national network of specialized and certified structures; the creation of synergies between these and research centers and, lastly, the promotion of a national plan for precision medicine.