White Susan M, Wondergem Annelotte P, Breet Isa, Dittmaier Maren, Bell Katrina, Richmond Christopher M, Hardikar Winita, Bhatia Kanika, Quinlan Catherine, Orchard David, D'Souza Areetha, Chazin Walter J, Smith Christopher, Sparkes Rebecca, Lam Simon, Carter Alexandra, Hopkin Robert J, Khendek Leticia, Sullivan Bonnie R, Becher Naja, Simonsen Anne Katrine W, Kvistgaard Helene, Dempsey Katherine, Miethke Alexander G, Gregersen Pernille Axél, Phillips Eliza, Luijsterburg Martijn S
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
Eur J Hum Genet. 2025 Jul 19. doi: 10.1038/s41431-025-01910-0.
DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.
DNA修复障碍是一组以进行性多系统表型为特征的疾病。明确这些疾病的新临床表现对于优化患者护理至关重要。ERCC1-XPF是一种多功能核酸内切酶，参与核苷酸切除修复（NER）和链间交联（ICL）修复。我们试图确定一种与双等位基因ERCC1变异和DNA修复受损相关的新型多系统表型。通过国际合作，我们从五个家庭中鉴定出七名携带双等位基因ERCC1变异的个体，包括p.Arg156Trp和p.Ala266Pro，他们表现出独特的临床表型。所有个体均有生长受限、光敏性以及肾脏和肝功能障碍。值得注意的是，三名儿童需要进行肝移植。四名儿童发生肝细胞癌，导致两人死亡，其中一人在接受阿霉素和顺铂治疗后死亡。年龄较大的个体表现出其他特征，包括共济失调、基底细胞癌、胰腺功能不全、卵巢功能衰竭、甲状腺功能减退和限制性肺病。使用患者来源的成纤维细胞进行的功能测定表明，ERCC1-XPF复合物显著不稳定，NER和ICL修复存在缺陷。然而，观察到残余的NER和ICL修复活性，提示错义变异具有亚效性作用，这些变异以纯合状态存在或与预测的功能丧失等位基因呈反式存在。我们将ERCC1-肝肾综合征定义为一种严重的多系统DNA修复障碍，具有高发病率和死亡率，包括小儿肝细胞癌的显著风险。我们提出了管理指南，强调癌症监测以及谨慎使用化疗以尽量减少治疗相关毒性。
