Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Front Immunol. 2023 Jan 30;13:1011580. doi: 10.3389/fimmu.2022.1011580. eCollection 2022.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including and is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon genomic rearrangements in aHUS and their impact on disease onset and outcomes.
In this study, we report the results of Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms.
We found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving alone or and (group A; n=14), while 30% exhibited rearrangements including only (group B; n=6). In group A, 6 patients presented hybrid genes, 7 patients carried duplications in the region that resulted either in the substitution of the last exon(s) with those of ( reverse hybrid gene) or in an internal duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the hybrid gene and one had 4 copies of and . Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the hybrid and a new internal duplication of .
In conclusion, these data highlight that uncommon SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the are associated with a poor prognosis but carriers respond to anti-complement therapy.
非典型溶血尿毒综合征（aHUS）是一种罕见的疾病，表现为微血管性溶血性贫血、血小板减少和急性肾衰竭，并与替代补体途径的失调有关。包括 和 在内的染色体区域富含重复序列，有利于已在数名 aHUS 患者中报道的基因组重排。然而，关于 aHUS 中罕见 的基因组重排的流行率及其对疾病发作和结局的影响的数据有限。
在这项研究中，我们报告了在包括 258 名原发性 aHUS 患者和 92 名继发性患者在内的大型队列中进行 拷贝数变异（CNV）分析和结构变异（SV）特征的结果。
我们在 8%的原发性 aHUS 患者中发现了罕见的 SV：70%的患者携带单独涉及 或 和 （A 组；n=14）的重排，而 30%的患者仅携带涉及 的重排（B 组；n=6）。在 A 组中，6 名患者出现 嵌合基因，7 名患者在 区域发生重复，导致最后 外显子（或多个外显子）被 取代（反向嵌合基因）或内部重复。在 A 组中，未经依库珠单抗治疗的大多数 aHUS 急性发作导致慢性 ESRD（12/13）；相比之下，抗补体治疗诱导了 4/4 例急性发作的缓解。在没有依库珠单抗预防的 7 个移植物中，6/7 个发生了 aHUS 复发，在有依库珠单抗预防的 3 个移植物中，没有发生 aHUS 复发。在 B 组中，5 名患者有 嵌合基因，1 名患者有 4 个拷贝的 和 。与 A 组相比，B 组患者的补体异常发生率更高，发病更早。然而，在没有依库珠单抗治疗的情况下，该组的 6 名患者中有 4 名患者完全缓解。在继发性疾病中，我们在 92 名患者中的 2 名中发现了罕见的 SV： 和 的新内部重复。
总之，这些数据表明，罕见的 SV 在原发性 aHUS 中很常见，在继发性疾病中很少见。值得注意的是，涉及 的基因组重排与不良预后相关，但携带者对抗补体治疗有反应。
