Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing

J Clin Pathol. 2018 Aug;71(8):687-694. doi: 10.1136/jclinpath-2017-204978. Epub 2018 Feb 17.


Aims: Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance.

Methods: Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients.

Results: We present design of NGS panel for 11 genes (TTR, FGA, APOA1, APOA2, LYZ, GSN, CST3, PRNP, APP, B2M, ITM2B) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population.

Conclusions: We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation.

Keywords: DNA; amyloid; haematology; molecular genetics; peripheral blood.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyloidosis, Familial / diagnosis
  • Amyloidosis, Familial / genetics*
  • Cardiomyopathy, Hypertrophic / diagnosis
  • Cardiomyopathy, Hypertrophic / genetics*
  • Computational Biology
  • Czech Republic
  • DNA Mutational Analysis / methods*
  • Female
  • Gene Expression Profiling / methods*
  • Gene Frequency
  • Genetic Markers
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Pilot Projects
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Reproducibility of Results
  • Risk Factors
  • Transcriptome*


  • Genetic Markers