Families with mutations in genes reported in hereditary
hematologic malignancy (HHM) syndromes
In Family1 and Family2 of our cohort, we identified germline mutations
in two genes known to confer inherited risk to development of MDS/AML:CEBPA and DDX41 . In particular, both sisters in Family1
harbored a likely pathogenic indel p.S21Tfs*139 in CEBPA . The
mutation is heterozygous in both sisters with VAF=51.9% and 50.8%,
respectively (Table 2). As expected for CEBPA-associated familial AML,
both sisters developed their disease at very young age (Table 1). We
performed somatic mutational analysis only for sister ID1 and detected
no somatic mutations (Table 3). However, this result may not be
significant since immunophenotypic analysis of BM aspirate used for NGS
showed less than 1% blast infiltration.
In Family2 both brothers had the germline heterozygous frameshift indel
p.K392Afs*66 in DDX41 , with VAF=51.7% and 48.6%, respectively.
This variant is currently annotated as VUS (Table 2). As for Family1, we
had tumor DNA available only for one brother. As often reported forDDX41 -associated familial AML, patient ID3 harbored also the
hotspot p.R525H somatic mutation for DDX41 (VAF=7.95%), together
with two other somatic mutations: the most common pathogenic variant inJAK2 p.V617F (VAF=3.56%) and the likely pathogenic mutation
p.P777H in DNMT3A (VAF=10.58%; Table 3).