They develop a new genomic medicine strategy improves the diagnosis of leukodystrophies


A study led by Aurora Pujol, geneticist and ICREA professor at the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL) and the Center for Biomedical Research in Network for Rare Diseases (CIBERER), has developed a new genomic medicine strategy that improves the leukodystrophies diagnostic rate, allows discovering new genes causing these diseases and broadens the clinical pictures described.

Leukodystrophies are a heterogeneous group of rare genetic diseases that affect myelin, the white matter of the brain. So far, more than 100 genes causing these pathologies have been identified. With current approaches, the molecular diagnosis is obtained in only half of the patients.

More than 100 types of leukodystrophies are known, with a prevalence of 1 in 7,000 births. In some types, those affected have clinical pictures at birth, while others may not cause symptoms until the child begins to walk, and others mainly affect adults. They are progressive and often fatal or severely disabling diseases.

The new strategy combines the analysis of exomes and genomes using a computational algorithm (a first step to artificial intelligence) that uses clinical data from patients to generate networks of interactomes (the molecular interactions between proteins) and prioritize variants.

He also performs functional studies on cells derived from patients to confirm variants of uncertain significance. In addition, neurologists are involved in the entire process, from the exhaustive description of the case to the selection of variants.

“Multidisciplinary teamwork is necessary to achieve success in most cases and we are fortunate to have the involvement of clinicians and the excellent sequencing services of the National Center for Genomic Analysis (CNAG)”, says Dr. Pujol .

The authors of this work, published in the journal ‘Neurology’, have carried out an analysis of 126 patients with leukodystrophies of different ages that had not been diagnosed with current clinical and molecular studies, including panels of NGS genes or clinical exomes, and have reached a diagnostic rate of 72 percent. In addition, they have identified new phenotypes, 9 new genes that cause leukodystrophies and several mutated genes that contribute to the clinical picture in 5 families.

This study confirms the great genetic heterogeneity of leukodystrophies, with 57 genes identified in the 91 diagnosed cases. Furthermore, many of these genes are not associated with the classical concept of leukodystrophies, so they were not included in the NGS panels that are currently used for their diagnosis.

“With our analysis, we have managed to reach the diagnosis in an average of six months, a great advance compared to the previous diagnostic odyssey of these cases, which lasted an average of 10 years. Beyond allowing genetic counseling of these families, molecular diagnosis has improved the clinical management of 32 percent of patients. In some cases, we have even started to test therapeutic options. In addition, we have expanded scientific knowledge about basic brain functions by being able to identify the genetic cause of new syndromes not described to date. Therefore, we propose a diagnostic paradigm shift to apply the whole exome (WES), or better genome sequencing (WGS) as a test of choice with the best cost / efficiency ratio in most cases of leukodystrophy “, emphasizes doctor Pujol.

This study was funded by the URD-Cat program, CIBERER, La Marató de TV3, the Carlos III Health Institute, the Hesperia Foundation and the CNAG. In addition, it has the collaboration of the Spanish Association against Leukodystrophies (ALE-ELA Spain). CIBERER researchers Luis Pérez Jurado and Rafael Artuch have participated, as well as members of clinical groups linked to CIBERER Mireia del Toro, Alfons Macaya and Luis González Gutiérrez-Solana, as well as Adolfo López de Munain (Hospital de Donostia and CIBERNED) and Sergio Aguilera (Hospital Complex of Navarra), among others.

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