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  • Title: An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia.
    Author: Rabacchi C, Wunsch A, Ghisellini M, Marino M, Pisciotta L, Bertolini S, Calandra S.
    Journal: Clin Chim Acta; 2009 Aug; 406(1-2):75-80. PubMed ID: 19467224.
    Abstract:
    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 c.1175 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.
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