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

C.A. Graham, B.P. McIlhatton, C.W. Kirk, E.D. Beattie, K. Lyttle, P. Hart, R.D.G. Neely, I.S. Young, D.P. Nicholls

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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 (
Original languageEnglish
Pages (from-to)331-340
Number of pages10
JournalAtherosclerosis
Volume182
Issue number2
DOIs
Publication statusPublished - 01 Oct 2005

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  • Impacts

    Identifying patients and families at risk of inherited high cholesterol

    Shirley Heggarty (Participant), Colin Graham (Participant), Wyatt Wright (Participant), Ian Young (Participant), Patricia M Hart (Participant), Maurice O'Kane (Participant), Paul Nicholls (Participant) & Norman Nevin (Participant)

    Impact: Health Impact

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