Family with a germline mutation in the LYST gene
In Family3 both brothers displayed a germline missense single-nucleotide mutation in the LYST gene, translating in p.R3398Q (Table 2). This variant is currently annotated as VUS and the functional consequences are unknown. Both siblings developed AML and somatic mutational analysis of their leukemic samples identified pathogenic variants. Brother ID5 harbored truncating pathogenic indels inASXL1 (p.R417*) and in RAD50 (p.N934Ifs*6), a likely pathogenic truncating indel in TET2 (p.L1721Ffs*24) and a VUS inIGFN1 (p.D2249G). Brother ID6 harbored the second most common somatic pathogenic variant in IDH2 , p.R172K, with VAF=36.9% (Table 3).
In order to reconstruct the genomic evolution of the disease in patient ID5, we exploited NGS analysis performed in our Institute on BM aspirates for clinical monitoring using the commercially available Oncomine Myeloid Research Assay. As shown in Figure 1A, there was partial response to treatment post-induction with disappearance of cells bearing TET2 p.L1721Ffs*24 and U2AF1 p.S34F variants, but there were no effects on the blasts harboring ASXL1 p.R417* andTET2 p.D77Tfs*18 mutations. The patient underwent CR post-allo TMB, however, unfortunately, he relapsed very rapidly with re-expansion of the same AML clone detected pre-transplant and appearance of a new mutation in TP53 , p.C141Y, that reached a VAF around 90%. The patient succumbed of disease less than 8 months after relapse.