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Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics
  1. Olaf R F Mook1,
  2. Martin A Haagmans1,
  3. Jean-François Soucy2,
  4. Judith B A van de Meerakker1,
  5. Frank Baas3,
  6. Marja E Jakobs3,
  7. Nynke Hofman1,
  8. Imke Christiaans1,
  9. Ronald H Lekanne Deprez1,
  10. Marcel M A M Mannens1
  1. 1Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Medical Genetics Division, CHU Sainte-Justine, Montréal, Canada
  3. 3Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr O R F Mook, Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; o.r.mook{at}


Background Genetic evaluation of cardiomyopathies poses a challenge. Multiple genes are involved but no clear genotype–phenotype correlations have been found so far. In the past, genetic evaluation for hypertrophic (HCM) and dilated (DCM) cardiomyopathies was performed by sequential screening of a very limited number of genes. Recent developments in sequencing have increased the throughput, enabling simultaneous screening of multiple genes for multiple patients in a single sequencing run.

Objective Development and implementation of a next generation sequencing (NGS) based genetic test as replacement for Sanger sequencing.

Methods and Results In order to increase the number of genes that can be screened in a shorter time period, we enriched all exons of 23 of the most relevant HCM and DCM related genes using on-array multiplexed sequence capture followed by massively parallel pyrosequencing on the GS-FLX Titanium. After optimisation of array based sequence capture it was feasible to reliably detect a large panel of known and unknown variants in HCM and DCM patients, whereby the unknown variants could be confirmed by Sanger sequencing.

Conclusions The rate of detection of (pathogenic) variants in both HCM and DCM patients was increased due to a larger number of genes studied. Array based target enrichment followed by NGS showed the same accuracy as Sanger sequencing.  Therefore, NGS is ready for implementation in a diagnostic setting.

  • Cardiomyopathy
  • Diagnostics
  • Genetics
  • Molecular genetics

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