Children with Severe Hypercholesterolemia Caused by a Pathogenic Mutation in &lt;i&gt;ABCG5&lt;/i&gt;

Tada, Hayato; Okada, Hirofumi; Nomura, Akihiro; Takamura, Masayuki; Kawashiri, Masa‐aki

doi:10.2169/internalmedicine.0050-22

Cited by 3 publications

(1 citation statement)

References 18 publications

(21 reference statements)

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“…Currently, more genetic variants in ABCG5 and ABCG8 are identified via the so-called panel sequencing covering these genes, particularly among patients with hypercholesterolemia. 5 6 7 8 However, the pathogenicity of the genetic variants of ABCG5 and ABCG8 is still challenging to determine because there are only a few data regarding this issue. In fact, The American College of Medical Genetics and Genomics (ACMG) guidance for the interpretation of sequence variants is typically used for assessing the pathogenicity of the genetic variations.…”

Section: Introductionmentioning

confidence: 99%

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia

Kojima,

Tada,

Nomura

et al. 2024

J Lipid Atheroscler

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Objective Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 ( ABCG5 ) or ATP-binding cassette sub-family G member 8 ( ABCG8 ). There are only few data on the pathogenicity of ABCG5 and ABCG8 . This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5–17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5–4.1] µg/mL) in 14 individuals. Conclusion The scheme proposed for assessing the pathogenicity of genetic variations ( ABCG5 and ABCG8 ) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

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Section: Introductionmentioning

confidence: 99%

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia

Kojima,

Tada,

Nomura

et al. 2024

J Lipid Atheroscler

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Assessment of ability of AlphaMissense to identify variants affecting susceptibility to common disease

Curtis

2024

Eur J Hum Genet

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An important issue in the analysis of rare variant association studies is the ability to annotate nonsynonymous variants in terms of their likely importance as affecting protein function. To address this, AlphaMissense was recently released and was shown to have good performance using benchmarks based on variants causing severe disease and on functional assays. Here, we assess the performance of AlphaMissense across 18 genes which had previously demonstrated association between rare coding variants and hyperlipidaemia, hypertension or type 2 diabetes. The strength of evidence in favour of association, expressed as the signed log p value (SLP), was compared between AlphaMissense and 43 other annotation methods. The results demonstrated marked variability between genes regarding the extent to which nonsynonymous variants contributed to evidence for association and also between the performance of different methods of annotating the nonsynonymous variants. Although AlphaMissense produced the highest SLP on average across genes, it produced the maximum SLP for only 4 genes. For some genes, other methods produced a considerably higher SLP and there were examples of genes where AlphaMissense produced no evidence for association while another method performed well. The marked inconsistency across genes means that it is difficult to decide on an optimal method of analysis of sequence data. The fact that different methods perform well for different genes suggests that if one wished to use sequence data for individual risk prediction then gene-specific annotation methods should be used.

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Cardiovascular disease risk in patients with elevated LDL-C levels: FH vs. non-FH

Huang,

Li,

Yang

et al. 2024

Front. Cardiovasc. Med.

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IntroductionCoronary artery disease (CAD) remains the primary cause of death worldwide, and familial hypercholesterolemia (FH) is a common disease that leads to CAD. This study aimed to explore the difference in CAD risk between FH and non-FH patients with high low-density lipoprotein cholesterol (LDL-C) levels.MethodsIndividuals (≥18 years) who underwent coronary angiography (CAG) from June 2016 to September 2020 were consecutively enrolled. Participants with LDL-C levels ≥4.0 mmol/L were ultimately included in this study. For all participants, next-generation sequencing was performed with expanded gene panels including 11 genes (LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, LIPA, LPA, APOBR, LRPAP1, and STAP1).ResultsA total of 223 individuals were included in this study. According to the CAG findings, 199 CAD patients and 24 non-CAD patients were included. The proportions of FH genes, regardless of whether 3 major genes or all 11 genes were sequenced, were not significantly different between the CAD and non-CAD groups (P > 0.05). In addition, all CAD patients were divided into a triple vessel disease (TVD) group and a non-TVD group. The TVD group had a greater proportion of patients with mutations in 3 FH major genes (P < 0.05). In addition, TC, LDL-C and modified LDL-C (MLDL-C) levels were higher and the estimated glomerular filtration rate (eGFR) was lower in the TVD group than in the non-TVD group (all P < 0.05). However, multivariate logistic regression analyses revealed that only the eGFR was an independent risk factor for TVD (OR 0.99; 95% CI: 0.98–1.00, P < 0.05). To eliminate the impact of the eGFR, subgroup analysis was conducted, and the results indicated that among CAD patients in the high-eGFR group, having FH mutations in 3 major genes was an independent risk factor for TVD (OR 3.00; 95% CI: 1.16–7.79, P < 0.05). In total, 104 FH-related mutations were detected in this study.ConclusionsFH mutation did not increase the rate of CAD in individuals with an MLDL-C level ≥4.0 mmol/L. However, among CAD patients (MLDL-C level ≥4.0 mmol/L) with almost normal renal function (≥87.4 ml/min/1.73 m2), the probability of enduring TVD in those with FH mutations in 3 major genes was 3.00 times greater than that in those without FH mutations.

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Children with Severe Hypercholesterolemia Caused by a Pathogenic Mutation in <i>ABCG5</i>

Cited by 3 publications

References 18 publications

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia

Assessment of ability of AlphaMissense to identify variants affecting susceptibility to common disease

Cardiovascular disease risk in patients with elevated LDL-C levels: FH vs. non-FH

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