Familial hypobetalipoproteinemia: Analysis of three Spanish cases with two new mutations in the APOB gene

Martín-Morales, R.; García-Díaz, Juan de Dios; Tarugi, Patrizia; González-Santos, Pedro; Saavedra-Vallejo, P.; Magnolo, Lucia; Mesa-Latorre, José María; Leo, Enza Di; Valdivielso, Pedro

doi:10.1016/j.gene.2013.08.049

Cited by 10 publications

(9 citation statements)

References 32 publications

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“…Mutations in the genes investigated also contribute to monogenic dyslipidaemias. Deleterious mutations in LDLR are the most common cause of FH [8,45,46]; loss of function variants in LDLRAP1 have been documented to cause high LDL-cholesterol levels with a recessive form of inheritance (38); variants in APOB have been known to cause both low and high LDLcholesterol levels [16,[47][48][49]; and loss of function variants that cause low LDL-cholesterol have been identified in PCSK9 [50][51][52]. In this study, two LDLRAP1 variants were associated with low LDL-cholesterol levels.…”

Section: Discussionmentioning

confidence: 60%

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations

et al. 2020

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Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.

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Section: Discussionmentioning

confidence: 60%

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations

et al. 2020

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“…The presence of this variant was confirmed in our laboratory. This variant is classified as pathogenic according to the ACMG guidelines and was previously described in a heterozygous FHBL patient ( Martín-Morales et al, 2013 ). The cascade screening performed on the index daughters revealed that one of them was carrying the APOB gene variant ( Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

Rare primary dyslipidaemias associated with low LDL and HDL cholesterol values in Portugal

et al. 2023

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Background: Dyslipidaemia represents a group of disorders of lipid metabolism, characterized by either an increase or decrease in lipid particles, usually associated with triglycerides, LDL cholesterol (LDL-C) and/or HDL cholesterol (HDL-C). Most hyperlipidaemias and HDL deficiencies confer an increased cardiovascular risk, while hypolipidaemia, such as abeta or hypobetalipoproteinemia, may present different manifestations ranging from poor weight progression to neurological manifestations. The aim of this study is to present 7 cases with rare dyslipidaemias associated with low LDL or low HDL cholesterol values, referred to our laboratory for the genetic identification of the cause of the dyslipidaemia.Methods: Lipid profile was determined for each individual in an automated equipment Integra Cobas (Roche). Molecular analysis was performed by NGS with a target panel of 57 genes involved in lipid metabolism (Sure select QXT, Agilent) and samples were run in a NextSEQ Sequencer (Illumina). Only genes associated to rare forms of low HDL-c or LDL-c were analysed for this work, namely: ABCA1, APOA1, LCAT, SCARB1, APOB, PCSK9, MTTP, SAR1B, and ANGPTL3. All rare variants (MAF<5%) found in these genes were confirmed by Sanger sequencing.Results and discussion: This study includes 7 index cases (IC), with the following clinical diagnoses: Fish Eye Disease (1), Hypoalphalipoproteinemia (1) and Abetalipoproteinemia (ABL) / Familial Hypobetalipoproteinemia (FHBL) (5). We have identified one IC with a compound heterozygosity in LCAT causing Fish Eye Disease and one IC with a variant in ABCA1 in homozygosity causing Tangier disease. We found variants causing homozygous FHBL in 2 IC, one of whom has an undescribed pathogenic variant in homozygosity in APOB (c.12087+1G>A) and the other is a possible compound heterozygous for APOB variants c.2604+1G>A and c.4651C>T/p.(Gln1551*). In two patients only a variant in heterozygosity (c.3365delG/p.(Gly1122Vfs*62) and c.11095A>T/p.(Arg3699*)). In the remaining patient, no variants were identified. NGS proved to be a fundamental key for genetic testing of rare lipid disorders, allowing us to find the genetic cause of disease in 6/7 patients with low HDL-c and LDL-c. Patients with these rare conditions should be identified as early as possible in order to minimize or prevent clinical manifestations. The unsolved case is still under investigation.

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“…Nonsynonymous, nontruncating APOB mutations have also been reported [5, 6]. It was reported that a nontruncated mutant protein can result in impaired secretion compared with the normal secretion of the mutant truncated proteins [7]. All of the previously reported nontruncating mutations are observed in residues 292–593.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is more likely that the disease causing mutation in the father and son is this exon 26 variant which does not affect apoB-48 but does cause premature truncation of the apoB-100 at residue 3778. In previous reports of heterozygotes for point mutations located in the exon 26 of the APOB gene it was found that the clinical manifestations of FHBL are dependent on the size of the resultant truncated apoB [7]. This variant likely accounts for the low LDL-cholesterol, total cholesterol, and apoB-100 observed in the father and son.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Mutations inSpatacsinandApolipoprotein BGenes in a Patient with Spastic Paraplegia and Hypobetalipoproteinemia

Peddareddygari¹,

Grewal

2015

Case Reports in Genetics

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Complicated hereditary spastic paraplegia (HSP) presents with complex neurological and nonneurological manifestations. We report a patient with autosomal recessive (AR) HSP in whom laboratory investigations revealed hypobetalipoproteinemia raising the possibility of a shared pathophysiology of these clinical features. A lipid profile of his parents disclosed a normal maternal lipid profile. However, the paternal lipid profile was similar to that of the patient suggesting autosomal dominant transmission of this trait. Whole exome sequence analysis was performed and novel mutations were detected in both the SPG11 and the APOB genes. Genetic testing of the parents showed that both APOB variants were inherited from the father while the SPG11 variants were inherited one from each parent. Our results indicate that, in this patient, the hypobetalipoproteinemia and spastic paraplegia are unrelated resulting from mutations in two independent genes. This clinical study provides support for the use of whole exome sequencing as a diagnostic tool for identification of mutations in conditions with complex presentations.

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Familial hypobetalipoproteinemia: Analysis of three Spanish cases with two new mutations in the APOB gene

Cited by 10 publications

References 32 publications

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations

Genetic associations between serum low LDL-cholesterol levels and variants in LDLR, APOB, PCSK9 and LDLRAP1 in African populations

Rare primary dyslipidaemias associated with low LDL and HDL cholesterol values in Portugal

Identification of Novel Mutations inSpatacsinandApolipoprotein BGenes in a Patient with Spastic Paraplegia and Hypobetalipoproteinemia

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