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

• Published in: Journal of clinical lipidology 2016-07, Vol.10 (4), p.944-952.e1
• Main Authors: Rabacchi, Claudio, PhD, Bigazzi, Federico, PhD, Puntoni, Mariarita, PhD, Sbrana, Francesco, MD, Sampietro, Tiziana, MD, Tarugi, Patrizia, PhD, Bertolini, Stefano, MD, Calandra, Sebastiano, MD
• Format: Article
• Language: English
• Subjects: Adult; APOB gene; Apolipoproteins B - genetics; Base Sequence; Cardiovascular; Female; Heterozygote; Homozygous familial hypercholesterolemia; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; In-frame deletion; LDL cholesterol; LDLR gene; Lipoproteins, HDL - blood; Lipoproteins, LDL - blood; Male; Missense mutations; Mutation; Mutation, Missense; Pedigree; Phenotype; Receptors, LDL - genetics; Siblings; Young Adult
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2016.04.005

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 ∼10 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_Gly396del)]. 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. Conclusions We report a rare event of 4 siblings found to be compound heterozygotes for 2 LDLR gene mutations but showing a different phenotype severity. The less severely affected siblings were carriers of a rare apoB missense variant.