Genetic and Clinical Spectrum of SAMD9 and SAMD9L Syndromes: from Variant Interpretation to Patient Management

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and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases.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.