title: A double heterozygote for familial hypercholesterolaemia and familial defective apolipoprotein B-100.
abstract: Autosomal dominant hypercholesterolaemia is genetically heterogeneous, but most commonly (approximately 93%) caused by mutations in low-density lipoprotein receptor (LDLR), where the disease is known as familial hypercholesterolaemia (FH), or apolipoprotein B-100 (APOB) (approximately 5.5%), where the disease is known as familial defective APOB (FDB), while in approximately 2% of patients the mutation is in the proprotein convertase subtilisin/kexin type 9 gene. Homozygous FH having inheritance of two LDLR mutations is a rare but recognized syndrome associated with an extreme hypercholesterolaemia and early-onset coronary artery disease. We present a 15-year-old girl with untreated total cholesterol levels of 8.8 mmol/L who was heterozygous for both the LDLR p.Leu479Pro and APOB p.Arg3527Gln mutation. Cascade testing confirmed the paternal origin of the LDLR mutation and revealed a maternal diagnosis of FDB. This case provides further evidence that the combined effect of an LDLR and an APOB mutation give rise to a phenotype more severe than either mutation alone and is more severe than homozygous FDB, but less severe than homozygous FH. It also highlights the need to consider the presence of additional mutations in families where relatives have varying phenotypes.
authors.affiliation: NE Thames Regional Molecular Genetics Laboratory, Great Ormond Street Hospital, Level 6 York House, 37 Queen Square, London WC1N3BH, UK. TayloA@gosh.nhs.uk
authors.forename: Alison
authors.initials: A
authors.lastname: Taylor
authors.forename: Graham
authors.initials: G
authors.lastname: Bayly
authors.forename: Kunjan
authors.initials: K
authors.lastname: Patel
authors.forename: Laura
authors.initials: L
authors.lastname: Yarram
authors.forename: Maggie
authors.initials: M
authors.lastname: Williams
authors.forename: Julian
authors.initials: J
authors.lastname: Hamilton-Shield
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Gail
authors.initials: G
authors.lastname: Norbury
mesh_terms: D000293:Adolescent; D000368:Aged; D053299:Apolipoprotein B-100 / Q000235:genetics*; D002648:Child; D003324:Coronary Artery Disease / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult
chemical_list: D053299:Apolipoprotein B-100