# Deep Intronic SVA_E Retrotransposition as a Novel Factor in Canavan Disease Pathogenesis

## TL;DR

This study identifies a new genetic factor in Canavan disease, a rare neurological disorder, that was previously undetected by standard diagnostic methods.

## Contribution

The discovery of a deep intronic SVA_E retrotransposon as a novel pathogenic variant in Canavan disease.

## Key findings

- Five patients with Canavan disease had an undetected second pathogenic variant in the ASPA gene.
- A deep intronic SVA_E element in intron 4 was identified using long-read sequencing.
- The SVA_E element is linked to a noncoding variant and causes efficient mRNA degradation.

## Abstract

Canavan disease (CD) is a rare autosomal recessive leukodystrophy caused by biallelic pathogenic variants in the ASPA gene. CD is characterized by developmental delay, macrocephaly, and abnormal muscle tone. The biochemical diagnosis is confirmed by increased N-acetylaspartic acid levels. The phenotypic presentation varies, with 85–90% of individuals exhibiting the severe, typical form, while 10–15% present with a milder, atypical form. Here we report on five patients with a clinical and biochemically proven diagnosis in whom a second pathogenic variant had not yet been identified. 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. Haplotype analysis of all patients showed linkage of the SVA_E element with a noncoding variant in intron 1. Functional characterization of the SVA_E element suggests that transcripts of the affected allele are prone to highly efficient mRNA degradation processes. These findings enhance the precision of genetic diagnostics and enable improved guidance for families as well as facilitating potential access to targeted therapies.