Involvement of MAP3K7 in FMD2 and CSCF, delineation of
genotype/phenotype correlations.
Abstract
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.