A new method for the rapid and inexpensive diagnosis of genetic diseases

A team of researchers from Lille has just developed a new method of sequencing the human genome which optimizes in terms of time and costs the determination of causal mutations in genetic diseases. Successfully tested in extreme childhood obesity associated with intellectual disability, this new methodology called CoDE-seq allows in a single step the sequencing of point mutations of all genes, and the very precise detection of chromosomal deletions and duplications. (called CNV). These results have been published in Molecular Metabolism.

Genetic diagnosis is lagging far behind in France. The reason is the lack of hospital teams in clinical genetics trained to analyze the genome correctly and quickly, the regulations, but also the current complexity and slowness of the “reimbursed” process of genetic exploration of patients with suspected genetic disease, which sequentially associates obsolete methods (eg karyotype), incomplete methods (eg DNA chips) and targeted DNA sequencing (generally only a few genes). This “obstacle course” is particularly slow (months to years), extremely expensive (thousands of euros) and only completely benefits a minority of patients. In 2018 in France, only a minority of patients benefited from full exploration.

The Lille team, in collaboration with the Swiss company Roche Diagnostics, and with doctors and researchers from the Catholic University of Lille, wanted to improve the care pathway for patients with genetic diseases by developing a method of more efficient, cheaper and above all faster genome analysis. CoDE-seq (for Copy number variation Detection and Exome sequencing) combines high-quality DNA screening of coding regions of 20,000 human genes (exome) with the sequencing of hundreds of thousands of 120-nucleotide probes consistently spanning l entire human genome allowing precise analysis of gene copy number (CNV) variants. Indeed, if in most cases we receive two copies of each gene, one from the father and the other from the mother (excluding sex chromosomes), there are many chromosomal regions or sometimes there is a lack of DNA (deletion ) or there is extra DNA (duplication). In either case, these abnormalities in the number of copies of genes (or parts of genes) can be responsible for genetic diseases, as are mutations that disrupt the function of proteins produced by mutated genes.

The Lille team started with the Roche Diagnostics commercial kit called MedExome which only explores the exons of human genes, to enrich it with probes covering all chromosomes, in collaboration with the American team at R & amp; D from Hamilton-based NimbleGen Roche. It studied 82 patients with a suspected monogenic form of obesity and / or intellectual disability, 40 of whom had been tested by the microarray method for the detection of CNV. Not only was CoDE-seq able to detect the 97 CNVs identified by chip, but also identified 84 more. Of these 82 patients, a molecular diagnosis could be demonstrated in 27 of them (with the identification of one or two genetic alterations that may be responsible for the disease). Half of these diagnoses are due to CNVs the other half to point mutations in the exome.
This new analysis of the increased exome is rapid (three weeks, DNA extraction and bioassay). IT included), and inexpensive (& lt; 500 € to date). It opens up promising perspectives for the molecular diagnosis of rare genetic diseases.

© Amélie Bonnefond & amp; Philippe Froguel

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