Identification of LAMP2 Mutations in Early-Onset Danon Disease With Hypertrophic Cardiomyopathy by Targeted Next-Generation Sequencing

Am J Cardiol. 2016 Sep 15;118(6):888-894. doi: 10.1016/j.amjcard.2016.06.037. Epub 2016 Jun 27.

Abstract

Danon disease is an X-linked disorder with the clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation. Early diagnosis of this disease remains a challenge, especially in the pediatric population. In this study, we developed a targeted panel-based next generation sequencing pipeline to identify mutations by sequencing of selected candidate genes in 136 pediatric patients with either hypertrophic cardiomyopathy (HC) or idiopathic dilated cardiomyopathy (IDC). This led to the identification of lysosome-associated membrane protein 2 (LAMP2) mutations in 4 of the 64 (6%) probands with HC, including 3 novel nonsense mutations (p.Q240X, p.S250X, and p.G22X). No LAMP2 mutation was detected in the other 72 probands with IDC. All 4 probands and one additional affected family member (2 men and 3 women) had an early-onset age and presented either HC alone or combined with Wolff-Parkinson-White syndrome and skeletal myopathy. Immunofluorescence staining and Western blot analysis revealed absent LAMP2 expression in both cardiac and skeletal muscle samples of the first proband and severely decreased LAMP2 expression in the skeletal muscle samples of the second proband. In conclusion, cardiomyopathy in the patients with Danon disease may occur during early childhood and tend to be HC rather than IDC in both affected men and women. Therefore, Danon disease should be considered as one of the leading causes of unexplained ventricular hypertrophy in pediatric patients. The inclusion of LAMP2 gene in cardiomyopathy genetic screening panels may contribute to early diagnosis of Danon disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Blotting, Western
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Female
  • Fluorescent Antibody Technique
  • Genotype
  • Glycogen Storage Disease Type IIb / genetics*
  • Glycogen Storage Disease Type IIb / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Lysosomal-Associated Membrane Protein 2 / genetics*
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Male
  • Muscle, Skeletal / metabolism
  • Mutation*
  • Myocardium / metabolism
  • Phenotype
  • Sequence Analysis, DNA
  • Wolff-Parkinson-White Syndrome / genetics

Substances

  • Codon, Nonsense
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2