title: Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations.
abstract: 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.
  
  
  
  The objective of the study was the molecular and phenotypic characterization of 4 siblings with severe hypercholesterolemia.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Claudio
authors: C
authors: Rabacchi
authors: Lipoapheresis Unit and Center for Inherited Dyslipidemias. Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors: Federico
authors: F
authors: Bigazzi
authors: Lipoapheresis Unit and Center for Inherited Dyslipidemias. Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors: Mariarita
authors: M
authors: Puntoni
authors: Lipoapheresis Unit and Center for Inherited Dyslipidemias. Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors: Francesco
authors: F
authors: Sbrana
authors: Lipoapheresis Unit and Center for Inherited Dyslipidemias. Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors: Tiziana
authors: T
authors: Sampietro
authors: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Patrizia
authors: P
authors: Tarugi
authors: Department of Internal Medicine, University of Genova, Genova, Italy. Electronic address: stefbert@unige.it.
authors: Stefano
authors: S
authors: Bertolini
authors: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: sebcal@unimore.it.
authors: Sebastiano
authors: S
authors: Calandra
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D001483:Base Sequence; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D035781:Siblings; D055815:Young Adult
chemical_list: D001055:Apolipoproteins B; C573412:LDLR protein, human; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL
keywords: APOB gene; Homozygous familial hypercholesterolemia; In-frame deletion; LDL cholesterol; LDLR gene; Missense mutations