SIGNATURES OF SOMATIC GENETIC RESCUE IN SAMD9/9L SYNDROMES: DIAGNOSTIC AND PROGNOSTIC UTILITY

Abstract

Introduction: Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) cause a novel bone marrow failure and pediatric myelodysplastic syndrome. Despite >400 patients reported, evaluating variants remains challenging with >70% of germline SAMD9/9Lmut classified as variants of uncertain significance, mainly due to heterogenous phenotypes and lack of functional assays. Many patients acquire compensatory clones including secondary SAMD9/9Lmut and UPD7q with loss of the mutant allele, along with maladaptive, stress-induced monosomy 7. Monosomy 7 poses unique surveillance challenges as it may disappear spontaneously over time, precluding the need for HSCT. Methods: We utilized our prospective somatic surveillance database to identify genetic patterns and evolution in SAMD9/9Lmut patients (median age 8 years). Using high-sensitivity myeloid gene panel and SNP array, we evaluated hematopoietic specimens of 23 patients with SAMD9/9L syndromes. For comparison, we analyzed a cohort of 132 patients with other BMF/MDS conditions. Serial analysis was performed in 39% (61/155) of patients for a median duration of 15.7 (1.4-53.2) months. Results: We found 33 somatic SAMD9/9Lmut in 61% (14/23), UPD7q in 26% (6/23), and monosomy 7 in 48% (11/23) of patients with germline SAMD9/9Lmut. Somatic SAMD9/9Lmut and UPD7q were not identified in the comparative cohort, resulting in 100% specificity and positive predictive value to rule-in germline SAMD9/9L syndromes. Notably, no patient (including monosomy 7 cases) developed advanced MDS, leukemia, or cancer driver mutations with up to 4.4 years of follow-up. Conclusions: Somatic SAMD9/9Lmut and UPD7q act as a “natural functional assay” confirming pathogenicity of germline SAMD9/9Lmut. Despite high rates of monosomy 7, leukemic progression is rare in SAMD9/9L syndromes.