Identification of a novel splicing‐altering LAMP2 variant in a Chinese family with Danon disease

Abstract

Aims

This study aimed to identify a novel splicing‐altering LAMP2 variant associated with Danon disease.

Methods and results

To identify the potential genetic mutation in a Chinese pedigree, whole‐exome sequencing was conducted in the proband, and Sanger sequencing was performed on the proband's parents. To verify the impact of the splice‐site variant, a minigene splicing assay was applied. The AlphaFold2 analysis was used to analyse the mutant protein structure. A splice‐site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified as a potential pathogenic variant. The minigene splicing revealed that this variant causes exon 6 to be skipped, resulting in a truncated protein. The AlphaFold2 analysis showed that the mutation caused a protein twist direction change, leading to conformational abnormality.

Conclusions

A novel splice‐site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified. This discovery may enlarge the LAMP2 variant spectrum, promote accurate genetic counselling, and contribute to the diagnosis of Danon disease.