Canavan disease
https://pmc.ncbi.nlm.nih.gov/articles/PMC12456746/#abstract1
Canavan disease is a rare, inherited neurological disorder that begins in early infancy and leads to progressive and irreversible loss of motor and cognitive abilities. It is caused by having two nonworking copies of the ASPA gene, which normally helps break down N-acetylaspartate. Although Canavan disease can often be diagnosed based on symptoms, brain imaging and biochemical testing, many affected individuals do not receive a clear genetic diagnosis using standard DNA sequencing methods. This limits access to emerging gene-based therapies and clinical trials. In this study, researchers investigated eight individuals who had clear clinical and biochemical evidence of Canavan disease but whose prior genetic testing was incomplete or negative. Using advanced long-read DNA sequencing, the team identified a large, previously hidden DNA insertion deep within the ASPA gene. This insertion, called an SVA_E retrotransposon, disrupts how the gene’s instructions are processed, leading to abnormal splicing and destruction of the gene’s message before a functional protein can be made. The same insertion was found in all eight individuals, either in two copies or paired with another known disease-causing ASPA variant. Analysis of large population databases revealed that this insertion is present across multiple ancestry groups and is likely the most common pathogenic variant associated with Canavan disease, more frequent than variants previously thought to be most common. This discovery reveals a major blind spot in routine genetic testing, which often misses large or repetitive DNA insertions. The study highlights the importance of reanalysing unresolved cases and adopting newer technologies, such as long-read sequencing and RNA studies, to improve diagnosis, carrier screening, and access to future treatments for Canavan disease and other rare genetic disorders.