Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations

BACKGROUND: Homozygous familial hypercholesterolemia is a rare clinical phenotype with a
variable expression, which is characterized by extremely elevated plasma low-density lipoprotein
(LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous
familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor
(LDLR) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR
function.
OBJECTIVE: The objective of the study was the molecular and phenotypic characterization of 4
siblings with severe hypercholesterolemia.
METHODS: The major LDL-related genes (LDLR, APOB, PCSK9, ANGPTL3, APOE, and
APOC3) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed
and sequenced.
RESULTS: The index cases were 24-year-old identical twin sisters with long-standing tendon
xanthomas and high low-density lipoprotein cholesterol (LDL-C w10 mmol/L) but no coronary
heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation
[p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel
24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C
6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of
exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396-
del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes
but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential
modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous
for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect.