Santacroce Rosa, D'Andrea Giovanna, Tiscia Giovanni Luca, Lassandro Giuseppe, d'Apolito Maria, Barcellona Doris, De Bonis Patrizia, Marongiu Francesco, Giordano Paola, Grandone Elvira, Margaglione Maurizio
Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.
Thrombosis and Haemostasis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", Viale Cappuccini, 71013 San Giovanni Rotondo, Italy.
Int J Mol Sci. 2025 Sep 10;26(18):8807. doi: 10.3390/ijms26188807.
Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the gene. This study investigated the correlation between FXI activity levels, genotype, and bleeding phenotypes. Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives, were evaluated. FXI:C plasma levels were measured. Sanger sequencing of was performed, and the pathogenicity of variants identified was assessed using in silico tools. FXI activity levels ranged widely (1-69%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype-phenotype correlation was observed. FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. This study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Further research is needed to clarify the complex genotype-phenotype relationships in FXI deficiency.
因子 XI（FXI）缺乏症，即丙型血友病，是一种罕见的出血性疾病，由于该基因的突变导致 FXI 蛋白水平降低或功能异常。本研究调查了 FXI 活性水平、基因型和出血表型之间的相关性。对来自意大利南部的 93 名被诊断为先天性 FXI 缺乏症的个体进行了临床和遗传特征评估，其中包括 39 例索引病例及其亲属。测量了血浆 FXI:C 水平。对该基因进行了桑格测序，并使用计算机工具评估了所鉴定变异的致病性。FXI 活性水平差异很大（1%-69%），大多数病例为杂合子，表现为中度缺乏。只有 12 名个体存在严重的 FXI 缺乏症，通常与纯合子或复合杂合子有关。出血症状从轻度到重度不等，31%的受试者出现出血症状，不过只有少数严重缺乏症患者经历过自发性或与手术相关的出血。桑格测序揭示了 24 种不同的该基因变异，主要为错义突变，其中包括三种新变异（p.Val89*、p.Leu306Pro 和 p.Trp515Gly）。常见突变包括 p.Glu135*和 p.Glu315Lys。变异分布于整个基因，没有特定结构域的聚集。未观察到明确的基因型-表型相关性。仅 FXI 水平不能可靠地预测出血风险，这突出了年龄、性别和临床病史等其他因素的影响。本研究强化了 FXI 缺乏症的等位基因和临床异质性，以及仅 FXI:C 水平在预测出血严重程度方面的有限效用。需要进一步研究以阐明 FXI 缺乏症中复杂的基因型-表型关系。
