LAMP2 variants in four Chinese children with Danon disease: clinical and molecular analysis in a monocentric cohort.

Background: Danon disease is an X-linked disorder caused by variants in the lysosome-associated membrane protein-2 (LAMP2) gene located on Xq24. Due to its inheritance in an X-chromosome dominant manner, males typically experience more severe manifestations than females.

Method: The whole exome sequencing was conducted on a cohort of 218 children diagnosed with hypertrophic cardiomyopathy; four children with hypertrophic cardiomyopathy carrying the LAMP2 variants were diagnosed at our centre. Variants in the LAMP2 gene were summarised, and their pathogenicity and conservation were analysed using bioinformatics methods. A retrospective analysis of genotype-phenotype associations was also conducted in conjunction with previously reported cases.

Results: Four patients with Danon disease were diagnosed in our single centre by gene sequencing; they all presented with myocardial hypertrophy as the initial manifestation. Both male patients manifested symptoms from infancy, while disease onset in the two female cases occurred below the average age reported for females. Through gene sequencing, a total of four variants were identified in these four patients, including one splicing variant: c.865-1G>C, one loss of heterozygosity variant: loss1 exon:4-9), one frameshift variant: c.973delG(p.(L325Wfs×21)), and one stop codon variant: c.467T>G(p.(L156*)).

Conclusion: This study identified four patients with LAMP2 gene variants, thereby enriching the documented genetic landscape of LAMP2-associated disorders. Bioinformatics analyses corroborated the pathogenicity of these variants. Additionally, we emphasised that women with suspected Danon disease should be thoroughly evaluated, and the possibility of implantable cardioverter defibrillator implantation and heart transplantation should be considered and discussed as early as possible.