Adenaeuer Anke, Ezigbo Eyiuche D, Fawzy Nazir Hanan, Barco Stefano, Trinchero Alice, Laubert-Reh Dagmar, Strauch Konstantin, Wild Philipp S, Lackner Karl J, Lämmle Bernhard, Rossmann Heidi
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
J Thromb Haemost. 2021 Jan;19(1):147-152. doi: 10.1111/jth.15137. Epub 2020 Nov 18.
Essentials Prekallikrein (PK) deficiency is a recessive trait with isolated aPTT prolongation. KLKB1 c.451dupT is common in Nigerians (7/600 alleles) and absent in a European group (0/600). To date, all genotyped PK-deficient patients of African ancestry were homozygous for 451dupT. Diagnostics of isolated aPTT prolongation in African descendants should include PK testing. ABSTRACT: Background Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Africans according to gnomAD (allele frequency 1.43%). Patients/Methods The most common African (c.451dupT) and European (c.1643G>A, p.Cys548Tyr) PK deficiency causing KLKB1 variants were analyzed in two population-based collectives of 300 Nigerian and 300 German subjects. Genome databases were evaluated for variant frequencies and ethnicity of the subjects. The geographic origin of PK-deficient cases due to 451dupT was assessed. Results Two of five patients with PK deficiency caused by homozygous 451dupT were African, one African American, one from Oman, and one of unknown origin. The frequency of 451dupT was 1.17% in the Nigerian collective (7/600 alleles); none had Cys548Tyr. Subjects with 451dupT were found among different Nigerian ethnicities. Both variants were absent in the European collective. Database research was compatible with these findings, even though mainly data of African Americans (451dupT: 1.12%-1.78%) was accessible. A relevant number of non-American Africans are included only in the 1000Genomes collective: 451dupT frequency was 1.29% in native Africans and 1.56% in African Caribbeans. Conclusions This study underlines the higher prevalence of PK deficiency among people with African descent compared to Europeans. In order to avoid delay of necessary surgical procedures in patients of African origin, diagnostic algorithms for isolated, unexplained, activated partial thromboplastin time prolongation in these subjects should include PK deficiency screening.
血浆前激肽释放酶（PK）缺乏症是一种隐性性状，表现为孤立的活化部分凝血活酶时间（aPTT）延长。KLKB1基因c.451dupT突变在尼日利亚人中很常见（600个等位基因中有7个），而在一组欧洲人群中不存在（600个等位基因中为0个）。迄今为止，所有基因分型的非洲血统PK缺乏症患者均为451dupT纯合子。对非洲后裔中孤立的aPTT延长进行诊断时应包括PK检测。摘要：背景 严重的血浆前激肽释放酶缺乏症（PK缺乏症）是一种常染色体隐性疾病，被认为非常罕见。最近我们报告称，在汇总基因组数据的数据库中列出的KLKB1基因中先前未被注意到的变异c.451dupT，p.Ser151Phefs*34，会导致PK缺乏症，并且根据gnomAD（等位基因频率1.43%），该变异在非洲人中很常见。患者/方法 在两个基于人群的队列中，对300名尼日利亚人和300名德国受试者中最常见的导致PK缺乏症的非洲（c.451dupT）和欧洲（c.1643G>A，p.Cys548Tyr）KLKB1变异进行了分析。评估了基因组数据库中变异频率和受试者的种族。评估了由451dupT导致的PK缺乏症病例的地理来源。结果 五名由451dupT纯合子导致PK缺乏症的患者中，两名是非洲人，一名是非裔美国人，一名来自阿曼，一名来源不明。451dupT在尼日利亚队列中的频率为1.17%（600个等位基因中有7个）；没有人携带Cys548Tyr变异。在不同的尼日利亚种族中都发现了携带451dupT变异的受试者。在欧洲队列中这两种变异均不存在。数据库研究与这些发现相符，尽管主要可获取的是非裔美国人的数据（451dupT：1.12%-1.78%）。相当数量的非美国非洲人仅被纳入1000基因组队列：451dupT在非洲原住民中的频率为1.29%，在非洲加勒比人中为1.56%。结论 本研究强调与欧洲人相比，非洲裔人群中PK缺乏症的患病率更高。为避免延误非洲裔患者必要的外科手术，针对这些受试者中孤立的、无法解释的活化部分凝血活酶时间延长的诊断算法应包括PK缺乏症筛查。
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