Sahoo Sushree S, Erlacher Miriam, Wlodarski Marcin W
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Blood. 2025 Jan 30;145(5):475-485. doi: 10.1182/blood.2022017717.
Sterile alpha motif domain-containing protein 9 (SAMD9) and SAMD9-like (SAMD9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germ line gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure, myelodysplasia, and monosomy 7. Nonhematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, whereas progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germ line missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease carry frameshift-truncating variants that are also GoF. Somatic genetic rescue occurs in two-third of patients or more and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to myelodysplastic syndrome (MDS)/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies, and outcome based on 243 published patients compiled in our registry, with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission vs disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.
含无菌α基序结构域蛋白9（SAMD9）和SAMD9样蛋白（SAMD9L）是编码对抗病毒蛋白的旁系同源基因，这些抗病毒蛋白对细胞增殖起负调控作用。杂合性种系功能获得性（GoF）SAMD9/9L变异会导致具有多种不同表现的多系统综合征。其共同特征包括血细胞减少、免疫缺陷、感染、骨髓衰竭、骨髓发育异常和7号染色体单体。非造血系统表现可累及几乎所有器官系统。生长发育障碍和肾上腺功能不全在SAMD9中较为典型，而进行性神经功能缺损是SAMD9L的特征。大多数患者（>90%）携带种系错义GoF变异。一组表现为SAMD9L相关炎症性疾病的患者携带移码截断变异，这些变异同样具有功能获得性。三分之二或更多患者会出现体细胞遗传挽救，包括7号染色体单体，其可能会自发消失（短暂性7号染色体单体）或进展为骨髓增生异常综合征（MDS）/白血病，以及具有体细胞SAMD9/9L补偿性突变或单亲二体7q（UPD7q）的适应性克隆，这两者均与病情缓解相关。本文基于我们登记的243例已发表患者，以及另外62例未发表病例的额外基因信息，研究了其临床和基因谱、治疗方法及预后情况。我们整合了SAMD9/9L综合征多样的临床表现和诊断挑战，以提高识别率并改善患者护理。我们强调了发病机制方面的知识空白，并强调了评估疾病缓解与疾病进展的基因监测的重要性。文中还介绍了变异分类以及检测体细胞SAMD9/9L突变和UPD7q的必要性。在专业中心进行多学科护理对于管理这些复杂疾病至关重要。未来的自然史研究，尤其是针对7号染色体单体患者的研究，将有助于制定基于证据的监测方案，并优化移植时机和结果。
