Journal
CLINICA CHIMICA ACTA
Volume 406, Issue 1-2, Pages 75-80Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.cca.2009.05.017
Keywords
Homozygous Familial Hypercholesterolemia; LDLR gene; Co-segregation analysis; Exon deletion; Alu sequence recombination
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Background: Familial Hypercholesterolemia (FH), the most common form of autosomal co-dominant hypercholesterolemia, is due to mutations in the LDLR gene, mostly minute or point mutations in the coding sequence. Methods: Analysis of LDLR gene was performed by direct resequencing and multiplex ligation-dependent probe amplification (MLPA). Results: LDLR gene resequencing showed that proband I.G., with the clinical diagnosis of homozygous FH, was homozygous for a mutation in exon 12 (c.1775 G>A, G571E) known to be pathogenic, and heterozygous for a mutation in intron 14 (c.2140 +5G>A). Proband's daughter with heterozygous FH carried only the intron 14 mutation. To explain this inconsistency we assumed that the proband was a carrier of a gene deletion. MLPA showed that the proband and her daughter were heterozygous for a deletion of exons 11 and 12. This explains the apparent homozygosity of the 0175 G>A mutation in the proband. Ex 11-12 deletion was linked to the c.2140 +5G>A mutation. Other FH patients, heterozygotes for c.2140 +5G>A, were found to carry the Ex 11-12 deletion found in the proband or other pathogenic mutations. Conclusions: Inconsistencies in the parent to offspring transmission of point mutations in LDLR gene may be due to a large deletion not detected by resequencing. (C) 2009 Elsevier B.V. All rights reserved.
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