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

AimsThis study aimed to identify a novel splicing-altering LAMP2 variant associated with Danon disease. Methods and resultsTo 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. ConclusionsA 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.

Automated summary

This study aimed to identify a novel splice-altering LAMP2 variant associated with Danon disease. Whole-exome sequencing and Sanger sequencing were conducted to identify the potential genetic mutation in a Chinese pedigree. 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 results revealed a truncated protein and conformational abnormality caused by this variant, expanding the LAMP2 variant spectrum and contributing to the diagnosis of Danon disease.