title: An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia.
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.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, I-41100 Modena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rabacchi
authors.forename: Alessia
authors.initials: A
authors.lastname: Wunsch
authors.forename: Margherita
authors.initials: M
authors.lastname: Ghisellini
authors.forename: Marco
authors.initials: M
authors.lastname: Marino
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
mesh_terms: D000328:Adult; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005260:Female; D023281:Genomics; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010290:Parents; D010641:Phenotype; D017354:Point Mutation; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D011973:Receptors, LDL