Medicina Molecular e Genética

A Case Report of a South Asian Family with Homozygous and Heterozygous Familial Defective APOB-100 Caused by p.(Arg3527Trp)

Abstract

Tracey I, Fairoozy RH, Humphries SE, Futema M and Hughes EA

Familial hypercholesterolemia (FH) is an autosomal dominant disorder most commonly caused by mutations in the gene for the Low-Density Lipoprotein (LDL) receptor (LDLR), but about 5% of patients in the UK with a clinical diagnosis of FH have a mutation in the gene for apolipoprotein B (APOB). This disorder is called Familial Defective APOB-100 (FDB), and while plasma total- and LDL-cholesterol levels overlap between patients with FDB and those with LDLR mutations, usually those with FDB present with a milder form of the disease, especially in homozygous FDB compared to LDLR mutation-caused FH. The most common mutation in APOB is p.(Arg3527Gln), but another APOB mutation p.(Arg3527Trp) has previously been identified in a family of South Asian origin. Here we describe a consanguineous marriage of parents of South Asian origin with both homozygous and heterozygous offspring with the APOB p.(Arg3527Trp) mutation. The mean untreated levels of LDL-cholesterol in the three heterozygous, Father and Mother (age 45 years) and a girl (age 9 years) were 5.5 mmol/l, 4.5 mmol/l, and 4.2 mmol/l respectively, while the mean untreated levels of LDL-cholesterol in the two homozygous boys (age 15 years and 11 years) were 6.2 mmol/l and 7.0 mmol/l respectively and this was reduced by ~30% on statin treatment. This confirms the milder phenotype and good response to statin therapy even for homozygous FDB.