Identifying a novel factor in Canavan disease pathogenesis

A new study in the peer-reviewed journal Human Gene Therapy reports on five patients with a clinical and biochemical diagnosis of Canavan disease, but were previously lacking a genetic diagnosis, in whom a novel variant was identified. Click here to read the article now.

Matthias Linke, from University Medical Center of the Johannes Gutenberg University Mainz, and Annette Bley, from University Medical Center Hamburg-Eppendorf, and coauthors stated that, “These findings enhance the precision of genetic diagnostics and enable improved guidance for families as well as facilitating potential access to targeted therapies.”

Canavan disease is a rare autosomal recessive leukodystrophy caused by biallelic pathogenic variants in the ASPA gene. In the current study, targeted long-read sequencing of the entire ASPA gene revealed an SVA_E retrotransposable element located in intron 4 that had been missed by standard short-read based diagnostic procedures. Retrotransposons are mobile genetic elements that use reverse transcription to move around within the genome.

“The SVA_E insertion leads to highly efficient mRNA degradation processes and thus offers potential innovative therapeutic approaches in the context of splice-switching antisense oligonucleotides,” stated the investigators. Furthermore, the findings of this study enable precise genetic counseling for affected patients and their families, particularly regarding reproductive planning.

“We typically think of rare genetic diseases as being caused by loss-of-function mutations or deletions in the coding sequence, which can be easily identified with today’s genomic technologies like short-read sequencing. However, this study helps us appreciate that genetic disorders can be caused by more complicated mechanisms that disrupt the function of the gene, and this awareness can lead to improved genetic screening to diagnose patients, better understanding of different forms of the disease based on the causative genetic variants, and more personalized medicine to treat patients based on the type and location of the variant,” says Managing Editor of Human Gene Therapy Thomas Gallagher, PhD, from the University of Massachusetts Chan Medical School.

About the Journal
Human Gene Therapy, the Official Journal of the European Society of Gene and Cell Therapy and eight other international gene therapy societies, was the first peer-reviewed journal in the field and provides all-inclusive access to the critical pillars of human gene therapy: research, methods, and clinical applications. The Journal is led by Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, and an esteemed international editorial board. Human Gene Therapy is available in print and online. Complete tables of contents and a sample issue are available on the Human Gene Therapy website.

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