Assises de Génétique 2024

Thrombotic microangiopathy (TMA) presents a diverse spectrum of nephrological disorders, marked by both genetic and non-genetic causes. Within this spectrum, complement-mediated TMA stands out as a significant genetically-driven subtype. A primary challenge in diagnosing TMA is the genomic complexity, particularly in regions with high sequence repetition, which standard short-read sequencing methods inadequately resolve. This complexity impedes rapid molecular diagnosis, crucial for starting targeted treatments like eculizumab or vitamin B12 therapy. To overcome this, our interdisciplinary team at Sorbonne University ICU has developed an innovative genomics analysis framework for TMA management in adult renal diseases. This framework combines Promethion Nanopore sequencing with adaptive sampling and the advanced SeqOne genomic platform. This integration significantly improves the detection and characterization of complex single nucleotide variants (SNVs) and structural variants (SVs), for understanding TMA's genetic basis. Our approach accelerates the genomic analysis, potentially identifying specific therapeutic targets in complement-mediated TMA in under three days. This rapid turnaround is essential for timely intervention and offers a competitive alternative to rapid short-read whole-genome sequencing in terms of cost and efficacy for TMA management. In conclusion, this novel genomic framework marks a significant advancement in precision medicine for TMA. It provides a faster, more accurate and cost-effective method for molecular diagnosis and targeted treatment in nephrology, enhancing patient care and treatment outcomes.

Long fragment sequencing has experienced significant maturation in recent years, both in terms of throughput and in the quality of the data generated. It is now possible to sequence entire human genomes at reasonable costs, so much so that certain genomics research projects have begun to use these technologies on series of individuals, or even populations. The use for the diagnosis of rare diseases is in its infancy, but some scientists predict a future of genomics based on long-read technologies. In this intervention, we present certain benefits of long-read sequencing, based on feedback from the analysis of genome data on Nanopore technology. In particular, the detection of balanced structure variations and the paradigm shift of phased approaches will be discussed, and the advantages on repeated regions such as pseudogenes, mobile elements and short-tandem repeats. Also, we review recent optimizations in the quality of raw long-read sequencing data, which are positioned as being able to detect virtually all types of variations in a single experiment, including small variations. While long-read genome sequencing is making its appearance in human genomics by filling many of the limitations of short-read sequencing, its initial use for the diagnosis of rare diseases is complex and will require logistical, technical and bioinformatic adaptations with the aim of increasing diagnostic yield.