You are here

Article Text

Article menu
Download PDFPDF
Online mutation report
The intron 14 2140+5G>A variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels
  1. R A Whittall1,
  2. S Matheus1,
  3. T Cranston2,
  4. G J Miller3,
  5. S E Humphries1
  1. 1Centre for Cardiovascular Genetics, The Rayne Institute, University College Hospital Medical School, University College London, 5 University Street, London WC1E 6JJ, UK
  2. 2Unit of Clinical Molecular Genetics, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK
  3. 3Medical Research Council Epidemiology and Medical Care Unit, Wolfson Institute of Preventative Medicine, Medical College of St Bartholomew's Hospital, Charterhouse Square, London EC1M 6BQ, UK
  1. Correspondence to:
 Dr S E Humphries, Centre for Cardiovascular Genetics, The Rayne Institute, University College Hospital Medical School, University College London, 5 University Street, London WC1E 6JJ, UK;
 rmhaseh{at}ucl.ac.uk

https://doi.org/10.1136/jmg.39.9.e57

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Familial hypercholesterolaemia (FH) is an autosomal dominant inherited lipoprotein disorder characterised by raised plasma low density lipoprotein (LDL) levels, xanthomas, premature coronary artery disease, and a family history of one or more of these.1 Homozygous FH occurs in one in a million people and they are severely affected, while heterozygotes are moderately affected and occur at a frequency of 1 in 500 in genetically heterogeneous populations. FH is caused by a mutation in the LDL receptor gene (LDLR) and over 700 have been reported to date (http://www.ucl.ac.uk/fh).2 However, it is not always possible to predict the pathogenicity or the clinical phenotype of a detected LDLR gene sequence variation. This is particularly the case for variants causing missense mutations, promoter regulatory element variations, or splice site junction variants where it is difficult to predict the degree or type of aberrant splicing.3

    Since 1996, a molecular genetic diagnostic service for FH has been running at Great Ormond Street Hospital.4 Over the last year several probands were found to have one of two variants in the LDLR gene, one in the promoter, −269G>T (numbering −1 from the base immediately upstream from the first base of the initiator methionine codon), which was originally reported as −175G>T, in a region known to contain important cis acting elements,5 and another at a moderately conserved base in a consensus splice site, 2140+5G>A, in intron 14. Both of these variants have been previously reported in FH patients.6,7 Here we determine the frequency of these variants in UK FH patients and investigate the likely pathogenicity of these two variants by determining their frequency in healthy non-FH subjects in the UK general population.

    MATERIALS AND METHODS

    An assay was designed for the −269G>T variant where an NruI restriction site was introduced into the PCR …

    View Full Text