Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia

Al‐Allaf, Faisal A.; Athar, Mohammad; Abduljaleel, Zainularifeen; Bouazzaoui, Abdellatif; Taher, Mohiuddin M.; Own, Rakan; Al-Allaf, Ahmad F.; Abumansour, Iman S.; Azhar, Zohor; Ba-hammam, Faisal A; Abalkhail, Hala; Al-Ashwal, Abdullah A.

doi:10.1038/hgv.2014.21

Cited by 20 publications

(5 citation statements)

References 16 publications

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“…Variants of the LDLR , APOB , PCSK9 genes, similar to those included in the study conducted in this region of Romania, were presented by several other authors, as indicated in Table 5 [ 1 , 2 , 3 , 4 , 5 , 7 , 8 , 9 , 10 , 11 , 15 , 16 , 30 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 59%

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

Vlad

Foia

Popescu

et al. 2021

JCM

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This study identifies the genetic background of familial hypercholesterolemia (FH) patients in Romania and evaluates the association between mutations and cardiovascular events. We performed a prospective observational study of 61 patients with a clinical diagnosis of FH selected based on Dutch Lipid Clinic Network (DLCN) and Simon Broome score between 2017 and 2020. Two techniques were used to identify mutations: multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The mutation rate was 37.7%, i.e., 23 patients with mutations were identified, of which 7 subjects had pathogenic mutations and 16 had polymorphisms. Moreover, 10 variants of the low-density lipoprotein receptor (LDLR) gene were identified in 22 patients, i.e., one variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in six patients, and one variant of the apolipoprotein B (APOB) gene in three patients. Of the LDLR gene variants, four were LDLR pathogenic mutations (c.81C > G, c.502G > A, c.1618G > A mutations in exon 2, exon 4, exon 11, and exon 13–15 duplication). The PCSK9 and APOB gene variants were benign mutations. The pathogenic LDLR mutations were significant predictors of the new cardiovascular events, and the time interval for new cardiovascular events occurrence was significantly decreased, compared to FH patients without mutations. In total, 12 variants were identified, with four pathogenic variants identified in the LDLR gene, whereas 62.3% of the study population displayed no pathological mutations.

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Section: Discussionmentioning

confidence: 59%

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

Vlad

Foia

Popescu

et al. 2021

JCM

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“…Most (more than 80%) of these variants were in LDLR . Two of these were found to be novel LDLR variants, c.1332dup (p.D445*) [ 18 ] and c.2026delG (p.G676Afs*33) [ 19 ]. Variations in PCSK9 are the second most common in Saudi Arabia, and variation in APOB among the least common [ 20 ].…”

Section: Disease Diagnosis and Awarenessmentioning

confidence: 99%

Homozygous Familial Hypercholesterolemia (HoFH) in Saudi Arabia and Two Cases of Lomitapide Use in a Real-World Setting

Mahzari

Zarif

2021

Adv Ther

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Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition in which mutations in key peptides involved in the low-density lipoprotein receptor (LDL-R) pathway result in markedly elevated levels of circulating LDL-cholesterol (LDL-C). Patients are at high risk of developing earlyonset atherosclerotic cardiovascular disease Moeber Mahzari and Hawazen Zarif are co-first authors of the manuscript.

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“…Similarly, based on these values, the incidence of homozygous FH has now been estimated at 1:160,000-300,000 rather than the historical estimate of 1:1,000,000 [1]. Notably, Saudi Arabia has few reports of prevalence and molecular characteristics of FH [2,[8][9][10][11][12]. However, FH is likely to have a higher predominance in Saudi Arabia than in other nations on the basis that consanguineous marriages represent up to 55% of all marriages in the country, as well as absence of either genetic screening programs or national registries for FH [13].…”

Section: Introductionmentioning

confidence: 99%

Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners

Alnouri

Al-Allaf

Athar

et al. 2020

Self Cite

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Background: Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients. Methods: Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing. Results: We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the LDLR alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the LDLR variant, two possibly damaging APOB variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in APOC3, PON2 and LPL genes respectively were identified. The PON2 gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA). Conclusions: The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.

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Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia

Cited by 20 publications

References 16 publications

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

Homozygous Familial Hypercholesterolemia (HoFH) in Saudi Arabia and Two Cases of Lomitapide Use in a Real-World Setting

Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners

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