A Mutational Hotspot in The LAMP2 Gene: Unravelling Intrafamilial Phenotypic Variation and Global Distribution of The c.877C>T Variant: A Descriptive Study

Document Type : Original Article


1 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 Rajaie Cardiovascular Medical and Research Centre, Iran University of Medical Sciences, Tehran, Iran

3 Growth and Development Research, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

5 Cardiogenetic Research Centre, Rajaie Cardiovascular Medical and Research Centre, Iran University of Medical Sciences, Tehran, Iran


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 determination
of genotype and phenotype of a newly diagnosed Iranian family with a unique phenotype due to a pathogenic variant
of 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, management
procedures, 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 variant
in 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 degrees
of left ventricular hypertrophy (LVH) that ranged from mild to severe. All patients exhibited typical cardiac conduction
abnormalities consistent with Danon disease. Four underwent heart transplants and survived. Skeletal muscle
involvement and cognitive impairment were observed in four patients each. The mean age of onset was 14 years. The
proband 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 in
managing affected patients, identify carriers, and assist with future family planning. This study highlights the intrafamilial
phenotypic variability of Danon disease. It is possible that variants of this gene may be frequent in Iran.


Main Subjects

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