Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate

Atherosclerosis. 2005 Oct;182(2):331-40. doi: 10.1016/j.atherosclerosis.2005.02.016.


Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n=68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n=130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845+11 c>g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (<10%) the genetic cause of the high cholesterol remains unknown, and other genes are still to be identified that could cause the clinical phenotype FH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins B / genetics
  • Base Sequence
  • Exons / genetics
  • Genetic Testing / methods*
  • Humans
  • Hyperlipoproteinemia Type II / diagnosis
  • Hyperlipoproteinemia Type II / genetics*
  • Introns / genetics
  • Molecular Sequence Data
  • RNA Splice Sites / genetics*
  • Receptors, LDL / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Apolipoproteins B
  • RNA Splice Sites
  • Receptors, LDL