PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■谷甾醇血症是一种罕见的常染色体隐性遗传疾病，由5三磷酸腺苷（ATP）结合盒亚家族G成员5（ABCG5）或ATP结合盒亚家族G成员8（ABCG8）的有害变体引起。关于ABCG5和ABCG8的致病性的数据很少。这项研究旨在提出一种确定变异致病性的方案，并对谷甾醇血症中的推定致病变异进行分类。
■本研究连续招募了377例高低密度脂蛋白胆固醇血症的日本患者（平均年龄：46.5±19.8岁，192名男性），他们在金泽大学医院从2016年至2021年对ABCG5或ABCG8（任何血脂异常的21个孟德尔脂质基因中）和血清谷甾醇水平进行了针对性测序。依泽替米贝治疗的患者血清谷甾醇水平除以0.79，考虑到这种药物的平均减少。ABCG5或ABCG8变体如果与血清谷甾醇水平≥5µg/mL相关，则被定义为推定致病性，如果与血清谷甾醇水平≥10µg/mL相关，则被定义为纯合。
■二十三个ABCG5或ABCG8变体（16个错觉，2废话，2移码，2删除，和1个剪接突变)被鉴定。根据我们的定义,在36个个体中发现了11种推定的致病变体（中位谷甾醇水平：10.1[6.5-17.1]µg/mL），在14个个体中发现了12种良性变体（中位谷甾醇：3.5[2.5-4.1]µg/mL）。
■为评估遗传变异（ABCG5和ABCG8）的致病性而提出的方案是有用的。使用这个方案，11推定致病性，并对ABCG5或ABCG中的12个良性变异进行了分类。
■本研究连续招募了377例高低密度脂蛋白胆固醇血症的日本患者（平均年龄：46.5±19.8岁，192名男性），他们在金泽大学医院从2016年至2021年对ABCG5或ABCG8（任何血脂异常的21个孟德尔脂质基因中）和血清谷甾醇水平进行了针对性测序。依泽替米贝治疗的患者血清谷甾醇水平除以0.79，考虑到这种药物的平均减少。ABCG5或ABCG8变体如果与血清谷甾醇水平≥5µg/mL相关，则被定义为推定致病性，如果与血清谷甾醇水平≥10µg/mL相关，则被定义为纯合。
■二十三个ABCG5或ABCG8变体（16个错觉，2废话，2移码，2删除，和1个剪接突变)被鉴定。根据我们的定义,在36个个体中发现了11种推定的致病变体（中位谷甾醇水平：10.1[6.5-17.1]µg/mL），在14个个体中发现了12种良性变体（中位谷甾醇：3.5[2.5-4.1]µg/mL）。
■为评估遗传变异（ABCG5和ABCG8）的致病性而提出的方案是有用的。使用这个方案，11推定致病性，并对ABCG5或ABCG中的12个良性变异进行了分类。
