An apparent inconsistency in parent to offspring transmission ofpoint mutations of LDLR gene in familial hypercholesterolemia

BackgroundFamilial 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.MethodsAnalysis of LDLR gene was performed by direct resequencing and multiplex ligation-dependent probe amplification (MLPA).ResultsLDLR 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.ConclusionsInconsistencies in the parent to offspring transmission of point mutations in LDLR gene may be due to a large deletion not detected by resequencing.