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The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

Jana Vandrovcova1, Ellen R A Thomas, Santosh S Atanur

  • 1MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|May 18, 2013
PubMed

Insights

Next-generation sequencing with target enrichment offers a sensitive and specific method for diagnosing familial hypercholesterolemia (FH). This approach improves molecular diagnosis rates for FH, aiding in early detection and treatment.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Disease

Background:

  • Familial hypercholesterolemia (FH) is a common genetic disorder leading to early-onset coronary heart disease.
  • Current diagnostic methods for FH are often costly and time-consuming, leaving many UK cases undiagnosed.
  • Molecular diagnosis is crucial for effective FH management and treatment with cholesterol-lowering drugs.

Purpose of the Study:

  • To evaluate the sensitivity and specificity of two next-generation sequencing (NGS) protocols for FH genetic diagnosis.
  • To compare the SureSelect Target Enrichment System and the Access Array platform for FH variant detection.
  • To assess the diagnostic yield of these NGS methods in a prospective cohort of suspected FH patients.

Main Methods:

  • Two target enrichment protocols were employed for library preparation: SureSelect and Access Array.
  • Next-generation sequencing was performed on samples from validation and prospective cohorts.
  • Sensitivity and specificity for short variant detection were calculated; large deletions/duplications were also assessed.

Main Results:

  • Both NGS protocols demonstrated 100% specificity for FH genetic diagnosis.
  • SureSelect achieved 100% sensitivity for short variants, while Access Array achieved 98%; only SureSelect detected large deletions/duplications.
  • In the prospective cohort, Access Array identified mutations in 67% of definite FH cases and 26% of possible FH cases.

Conclusions:

  • Target enrichment combined with NGS is a viable strategy for molecular diagnosis of familial hypercholesterolemia.
  • Implementing these NGS assays can enhance cost-effectiveness and increase the number of patients receiving a molecular FH diagnosis.
  • Improved diagnostic capabilities can facilitate timely intervention for individuals with suspected FH.
Abstract

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