Mutation detection in Croatian patients with Familial Hypercholesterolemia
Article first published online: 6 NOV 2012
© 2012 Blackwell Publishing Ltd/University College London
Annals of Human Genetics
Volume 77, Issue 1, pages 22–30, January 2013
How to Cite
Pećin, I., Whittall, R., Futema, M., Sertić, J., Reiner, Ž., Leigh, S. E. A. and Humphries, S. E. (2013), Mutation detection in Croatian patients with Familial Hypercholesterolemia. Annals of Human Genetics, 77: 22–30. doi: 10.1111/j.1469-1809.2012.00735.x
- Issue published online: 21 DEC 2012
- Article first published online: 6 NOV 2012
- Manuscript Accepted: 25 AUG 2012
- Manuscript Received: 18 MAY 2012
- British Heart Foundation
- MRC CASE award
- International Atherosclerosis Society
- Coronary heart disease;
- familial hypercholesterolemia;
- high-resolution melting method;
Familial hypercholesterolemia (FH) is caused by mutations in the genes for LDLR, APOB or PCSK9, and identification of the causative mutation provides definitive diagnosis so that the patient can be treated, their relatives tested and, therefore, premature heart disease prevented.
DNA of eight unrelated individuals with clinically diagnosed FH were analyzed using a High-Resolution Melting method (HRM) for the LDLR gene (coding region, promoter and intron/exon boundaries), the APOB gene (part exon 26) and the PCSK9 gene (exon7). Variations found were sequenced and the effect on function of confirmed variants examined using predictive algorithms. Gross deletions and insertions were analysed using MLPA.
Three novel LDLR variants were found, p.(S470C), p.(C698R) and c.2312–2A>C. All were predicted to be pathogenic using predictive algorithms. Three previously reported disease-causing mutations were identified (p.(G20R), p.(N272T) and p.(S286R); the latter was also carried by a hypercholesterolaemic relative. One patient carried the pathogenic APOB variant p.(R3527Q). No large LDLR deletions nor insertions were found, neither were any PCSK9 variants identified.
HRM is a sensitive method for screening for mutations. While the causative mutation has been identified in 88% of these clinically defined FH patients, there appears to be a high degree of allelic heterogeneity in Croatian patients.