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

Introduction

Germline SAMD9 and SAMD9L mutations (SAMD9/9L^mut) cause a novel bone marrow failure and pediatric myelodysplastic syndrome. Despite >400 patients reported, evaluating variants remains challenging with >70% of germline SAMD9/9L^mut classified as variants of uncertain significance, mainly due to heterogenous phenotypes and lack of functional assays. Many patients acquire compensatory clones including secondary SAMD9/9L^mut 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 SAMD9/9L^mut 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 SAMD9/9L^mut in 61% (14/23), UPD7q in 26% (6/23), and monosomy 7 in 48% (11/23) of patients with germline SAMD9/9L^mut. Somatic SAMD9/9L^mut 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 SAMD9/9L^mut and UPD7q act as a “natural functional assay” confirming pathogenicity of germline SAMD9/9L^mut. Despite high rates of monosomy 7, leukemic progression is rare in SAMD9/9L syndromes.