Key result
A novel LAMP2 p.G93R missense mutation was identified in a proband with mild Danon disease and three family members, leading to protein destabilization and reduced LAMP2 expression.
Why the study?
Danon disease is an X-linked dominant multisystem disorder resulting from LAMP2 mutations, prompting genetic evaluation of a proband presenting with mild disease and a familial hypertrophic cardiomyopathy phenotype.
Case Report (n=4)
Identifies a novel LAMP2 p.G93R mutation associated with mild Danon disease presenting as familial HCM, highlighting the importance of molecular diagnostics in HCM patients.
Alerts clinicians to LAMP2 testing in mild Danon-like cases; leaves open broader screening and penetrance estimates.
BACKGROUND: Danon disease (DD) is an X-linked dominant multisystem disorder that is associated with cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability. It results from mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. METHODS: Herein, a proband with a mild DD case presenting with a familial hypertrophic cardiomyopathy (HCM) phenotype and additional family members were evaluated. Exome sequencing and Sanger sequencing were performed to explore the genetic basis of DD in the proband. Segregation, in silico, and functional analyses were carried out to explore potential pathogenicity in the candidate mutation. RESULTS: Exome sequencing and Sanger sequencing identified one novel missense mutation (p.G93R) in the LAMP2 gene in the proband, and this mutation was also identified in three other family members. In silico analysis of LAMP2 predicted that the mutation causes a conformational change and subsequent protein destabilization. Furthermore, functional examination showed that mutation carriers have a significant reduction in LAMP2 expression, which supports that the mutation is pathogenic. Moreover, skewed X chromosome inactivation (XCI) was identified in one female mutation carrier, thus suggesting that skewed XCI may be the reason why this individual escaped the pathogenic influence of the mutation. CONCLUSION: These findings will aid in diagnosing DD patients carrying this LAMP2 mutation that presents with a HCM phenotype. Furthermore, this study illustrates the importance of utilizing a molecular diagnostic approach in HCM patients and is the first study to report a LAMP2 p.G93R mutation associated with mild DD and identify that XCI serves a protective role in DD etiology.
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Xu et al. (2019) conducted a case report in Danon disease / familial hypertrophic cardiomyopathy (n=4). LAMP2 p.G93R mutation was evaluated on Identification of genetic basis and functional impact of the mutation. A novel LAMP2 p.G93R missense mutation was identified in a proband with mild Danon disease and three family members, leading to protein destabilization and reduced LAMP2 expression.
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