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

Lookup NU author(s): Dr R Neely


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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. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Publication metadata

Author(s): Graham CA, McIlhatton BP, Kirk CW, Beattie ED, Lyttle K, Hart P, Neely RDG, Young IS, Nicholls DP

Publication type: Article

Publication status: Published

Journal: Atherosclerosis

Year: 2005

Volume: 182

Issue: 2

Pages: 331-340

ISSN (print): 0021-9150

ISSN (electronic): 1879-1484

Publisher: Elsevier Ireland Ltd


DOI: 10.1016/j.atherosclerosis.2005.02.016


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