Cell Journal (Jan 2024)
A Mutational Hotspot in The LAMP2 Gene: Unravelling Intrafamilial Phenotypic Variation and Global Distribution of The c.877C>T Variant: A Descriptive Study
Abstract
Objective: Danon disease is defined by a clinical trio of cardiomyopathy, skeletal myopathy, and cognitive impairment.It results from the lysosomal-associated membrane protein-2 (LAMP2) gene variants. The aim of study is determinationof genotype and phenotype of a newly diagnosed Iranian family with a unique phenotype due to a pathogenic variantof the LAMP2 gene along with a phenotypic comparison of all reported patients.Materials and Methods: In this descriptive study, we evaluated the demographic data, clinical features, managementprocedures, as well as genetic analysis of both patients in this newly diagnosed family. Whole genome sequencing(WGS) and in silico structural and functional predictions were applied. A comprehensive search of the c.877C>T variantin LAMP2 was conducted using the PubMed, Google Scholar, VarSome, ClinVar, Human Gene Mutation Database(HGMD), and Franklin databases to identify any genotype-phenotype correlations.Results: Nine patients were carriers of the c.877C>T variant. All patients were male, and displayed variable degreesof left ventricular hypertrophy (LVH) that ranged from mild to severe. All patients exhibited typical cardiac conductionabnormalities consistent with Danon disease. Four underwent heart transplants and survived. Skeletal muscleinvolvement and cognitive impairment were observed in four patients each. The mean age of onset was 14 years. Theproband in this study exhibited an earlier onset of cardiac symptoms.Conclusion: Genetic analysis is the preferred diagnosis approach for Danon disease and can assist families inmanaging affected patients, identify carriers, and assist with future family planning. This study highlights the intrafamilialphenotypic variability of Danon disease. It is possible that variants of this gene may be frequent in Iran.
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