Myelodysplastic syndromes (MDS) are poorly understood and rare hematologic malignancies in children. In recent years, several germline mutations have been implicated in a subset of familial cases of MDS, other myeloid neoplasms or bone marrow failure syndromes including mutations in GATA2, ETV6 and DDX41. 1, 2 However, for some families, such as those first reported nearly 30 years ago, 3, 4 who present with MDS and monosomy 7 (OMIM 252270), the predisposing genetic alteration has remained elusive. Here we report our findings on a family without historical suggestions of MDS/AML predisposition but with three siblings with monosomy 7 and MDS.

A 4-year-old male (proband/SJ015856/Sibling 1) was found to have severe neutropenia, macrocytosis and thrombocytopenia (absolute neutrophil count= 400/mm3, mean corpuscular volume= 101.7 fl, platelets= 111× 109/l). Bone marrow evaluation revealed hypocellularity with trilineage dysplasia and 1% blasts (Figure 1a). His 3-year-old sister (SJ015855/Sibling 2) also had low peripheral cell counts and bone marrow dysplasia, while his youngest brother (14-month-old/SJ018228/Sibling 3) had normal peripheral counts and a hypocellular bone marrow with megakaryocytic dysplasia. Cytogenetic analysis was significant for monosomy 7 in all siblings (Figure 2; Supplementary Figure 1) and thus all three were diagnosed with refractory cytopenia of childhood. All three siblings had a transient thrombocytopenic phase at birth requiring a platelet transfusion, but had otherwise normal developmental histories and stature-for-age (at or above the 75th percentile). The proband was born with severe hypospadias and a bifid scrotum requiring multiple corrective surgeries without any bleeding complications. A karyotype during the neonatal period demonstrated a normal male karyotype. No other congenital abnormalities were noted in the siblings. Chromosome breakage studies for Fanconi Anemia were negative. The two eldest siblings have been treated with matched, unrelated donor bone marrow transplants, while the youngest sibling remains asymptomatic with normal peripheral blood counts and is monitored annually. Bone marrow samples from the three siblings were banked for research after informed consent was obtained. All studies were approved by the Institutional Review Board at St Jude Children’s Research Hospital. Cryopreserved marrow samples were flowsorted into lymphocyte (source of ‘germline’DNA), as an alternate source of germline DNA was not available, 5 and bulk myeloid populations. Whole exome sequencing was performed on paired tumor/normal samples from the three siblings. Whole