SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in >2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to 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and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases.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 versus 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.

中文翻译：

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SAMD9 和 SAMD9L 综合征的遗传和临床谱：从变异解释到患者管理。


SAMD9 和 SAMD9L （SAMD9/9L） 是编码抗病毒蛋白的旁系同源基因，可负向调节细胞增殖。杂合子种系功能获得性 （GoF） SAMD9/9L 变体可引起表现多样的多系统综合征。统一的特征是血细胞减少、免疫缺陷、感染、骨髓衰竭 （BMF）、骨髓增生异常 （MDS） 和 7 型单体。非造血表现几乎可以影响每个器官系统。生长障碍和肾上腺皮质功能减退是 SAMD9 的典型特征，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。表现为 SAMD9L 相关炎症性疾病 （SAAD） 的患者亚组携带移码截短变异，这些变异也是 GoF。体细胞基因挽救发生在 >2/3 的患者中，涉及 7 型单体，它可能自发消失（短暂性 7 型）或进展为 MDS/白血病，以及具有体细胞 SAMD9/9L 代偿突变或单亲 7q 型二体 （UPD7q） 的适应性克隆，两者均与缓解相关。本手稿根据我们登记处汇编的 243 名已发表的患者以及 62 名未发表病例的额外遗传信息，检查了临床和遗传谱、疗法和结果。我们整合了 SAMD9/9L 综合征的不同临床表现和诊断挑战，以提高识别度并改善患者护理。我们强调了病理机制方面的知识差距，并强调了遗传监测评估疾病缓解与疾病进展的重要性。提供了对变体管理以及体细胞 SAMD9/9L 突变和 UPD7q 测试必要性的见解。专科中心的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，尤其是对 7 型单体患者的研究，将有助于制定循证监测方案并优化移植时间和结果。