Germline 3q21 chromosome deletions result in a rare multi-system condition. Of the 14 cases of germline 3q21 deletion syndrome reported, 2 have been reported to develop myelodysplastic syndrome necessitating allogeneic HCT (our patient and one other). Our patient was treated with an allogeneic, matched sibling hematopoietic cell transplantation. Patients with 3q21 deletion have a predilection for myelodysplastic syndrome, likely due to GATA2 deletion. We recommend frequent complete blood count evaluation with annual bone marrow aspiration to monitor for development of MDS in patients with 3q21 deletion.

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.