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

Rabacchi, Claudio; Bigazzi, Federico; Puntoni, M.; Sbrana, Francesco; Sampietro, Tiziana; Tarugi, Patrizia; Bertolini, Stefano; Calandra, Sebastiano

doi:10.1016/j.jacl.2016.04.005

Cited by 10 publications

(5 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a study of 177 untreated FH patients in the United Kingdom, Humphries et al (8) demonstrated a large range of total cholesterol levels ranging from just above 5 mmol/l to over 15 mmol/l. Mutations in genes that are known to reduce LDLc, particularly APOB mutations known to cause hypobetalipoproteinemia but also mutations in PCSK9, APOE, and ANGPTL3 were found to reduce LDLc in some FH patients (9)(10)(11)(12) These and other studies (13) demonstrate that the large variability in phenotypic FH is influenced by both genetic and environmental modifiers.…”

mentioning

confidence: 64%

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

Winther

Shpitzen

Yaacov

et al. 2019

Journal of Lipid Research

View full text Add to dashboard Cite

Supplementary key words low density lipoprotein • genetics • cholesterol metabolism • diseases/dyslipidemia • gene expression/polymorphisms • genes in lipid dysfunction • low density lipoprotein/assembly • low density lipoprotein cholesterol • familial hypercholesterolemia • single nucleotide polymorphism • microsomal triglyceride transfer protein Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by a high LDL cholesterol (LDLc) content in the serum. FH occurs in one in 250500 in heterozygous (HTZ) form and one in a million in homozygous (HMZ) form (1). In most cases, the disorder results from mutations in the LDL receptor (LDLR) gene. Mutations in the APOB-100 gene and the recently identified proprotein convertase subtilisin/kexin type 9 (PCSK9) gene result in phenocopies of the disease (2). Over a thousand different mutations in LDLR have been recorded to date. Owing to the high content of LDL in the blood, this disorder predisposes patients to early atherosclerosis, premature coronary heart disease, cerebrovascular accidents, calcification of cardiac valves leading to their dysfunction, and even early death. It is thought that at least 5% of all early myocardial infarctions are in FH individuals. Although FH is caused by mutations in single genes, individuals with FH show striking phenotypic variability.

show abstract

mentioning

confidence: 64%

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

Winther

Shpitzen

Yaacov

et al. 2019

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…This p.Asp19His variant was reported among Hispanic subjects and was significantly associated with lower concentrations of plasma sterol concentration, suggesting that it may alter the function of ABCG8 by increasing its transporter function [42]. An association of this variant with plasma cholesterol concentration could not be observed [43] and this may explain the normal cholesterol level in the mother and eldest brother who are carriers of this variant. Our study showed that the twins who had both mutations (in LDLR and ABCG8 genes) had a more severe clinical phenotype with a higher TC and LDL-c compared to their father, grandfather and hypercholesterolemic brother who only had LDLR mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Miyagi et al reported a dichorionic diamniotic twin with compound heterozygous LDLR mutation causing FH 42 . Rabacchi et al on the other hand reported identical twins with compound heterozygous FH with two LDLR gene mutations [43].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review

et al. 2019

View full text Add to dashboard Cite

Background Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease with an autosomal dominant mode of inheritance. It is characterised by raised serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c), leading to premature coronary artery disease. Children with FH are subjected to early and enhanced atherosclerosis, leading to greater risk of coronary events, including premature coronary artery disease. To the best of our knowledge, this is the first report of a pair of monochorionic diamniotic identical twins with a diagnosis of heterozygous FH, resulting from mutations in both LDLR and ABCG8 genes. Case presentation This is a rare case of a pair of 8-year-old monochorionic diamniotic identical twin, who on family cascade screening were diagnosed as definite FH, according to the Dutch Lipid Clinic Criteria (DLCC) with a score of 10. There were no lipid stigmata noted. Baseline lipid profiles revealed severe hypercholesterolaemia, (TC = 10.5 mmol/L, 10.6 mmol/L; LDL-c = 8.8 mmol/L, 8.6 mmol/L respectively). Their father is the index case who initially presented with premature CAD, and subsequently diagnosed as FH. Family cascade screening identified clinical FH in other family members including their paternal grandfather who also had premature CAD, and another elder brother, aged 10 years. Genetic analysis by targeted next-generation sequencing using MiSeq platform (Illumina) was performed to detect mutations in LDLR, APOB100, PCSK9, ABCG5, ABCG8, APOE and LDLRAP1 genes. Results revealed that the twin, their elder brother, father and grandfather are heterozygous for a missense mutation (c.530C > T) in LDLR that was previously reported as a pathogenic mutation. In addition, the twin has heterozygous ABCG8 gene mutation (c.55G > C). Their eldest brother aged 12 years and their mother both had normal lipid profiles with absence of LDLR gene mutation. Conclusion A rare case of Asian monochorionic diamniotic identical twin, with clinically diagnosed and molecularly confirmed heterozygous FH, due to LDLR and ABCG8 gene mutations have been reported. Childhood FH may not present with the classical physical manifestations including the pathognomonic lipid stigmata as in adults. Therefore, childhood FH can be diagnosed early using a combination of clinical criteria and molecular analyses.

show abstract

“…1 Homozygous or compound heterozygous pathogenic variants in other genes, such as apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), or the LDLR gene, are found in patients with homozygous familial hypercholesterolemia (HoFH), demonstrating a clinical phenotype consistent with ARH 2 -extremely high LDL-C levels, very extensive cutaneous or tendon xanthomas, aortic stenosis, and premature atherosclerotic CVD. 1,2 However, owing to currently unknown reasons, patients with HoFH have a greatly reduced life expectancy, higher rates of premature atherosclerotic CVD (including risks of myocardial infarction before the age of 20 years), and an even worse response to lipid-lowering treatment compared to patients with ARH. [1][2][3][4][5] The prevalence of FH is commonly reported as 1 in 500 individuals.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 However, owing to currently unknown reasons, patients with HoFH have a greatly reduced life expectancy, higher rates of premature atherosclerotic CVD (including risks of myocardial infarction before the age of 20 years), and an even worse response to lipid-lowering treatment compared to patients with ARH. [1][2][3][4][5] The prevalence of FH is commonly reported as 1 in 500 individuals. 6 Recent studies showed the prevalence of heterozygous FH consistent with the ratios of 1:200-1:250; by extrapolation, HoFH may affect up to 6 individuals per million (or 1 in 160,000-300,000).…”

Section: Introductionmentioning

confidence: 99%

Autosomal recessive hypercholesterolemia: Case report

Petrulionienė

Gargalskaitė

Mikštienė

et al. 2019

Journal of Clinical Lipidology

View full text Add to dashboard Cite

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

Cited by 10 publications

References 34 publications

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review

Autosomal recessive hypercholesterolemia: Case report

Contact Info

Product

Resources

About