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 inMAP3K7 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 inMAP3K7 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.
Keywords: MAP3K7, frontometaphyseal dysplasia type 2,
cardiospondylocarpofacial syndrome , Noonan Syndrome
Introduction
The MAP3K7 gene (Mitogen-Activated Protein 3 Kinase 7) encodes
transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which
plays a vital role in innate and adaptive immunity by regulating
inflammatory responses and regulating cell differentiation, cell
survival and apoptosis
(Dai et al., 2012; Yu et al., 2014). Variants in MAP3K7 have been
associated with two autosomal dominant conditions; frontometaphyseal
dysplasia type 2 (FMD2) caused by recurrent gain-of-function variants
(Wade et al., 2016), and cardiospondylocarpofacial syndrome (CSCF)
caused by individual variants most often considered to induce
loss-of-function
(Le Goff et al., 2016).
FMD is a progressive skeletal dysplasia characterized by sclerosis of
the skull, joint contractures and under-modeled long bones, scoliosis
and prominent supraorbital ridges. Other features include hypertelorism,
down-slanting palpebral fissures, broad nasal bridge, full cheeks,
micrognathia, hydronephrosis, cleft palate, hearing loss, ulnar
deviation of the hands, camptodactyly, wrist contractures, long fingers,
structural cardiac defect and keloid scars (Costantini et al., 2018).
FMD is caused by gain-of-function variants in FLNA , TAB2and MAP3K7
(Robertson, 2004; Giuliano et al., 2005; Wade et al., 2016; 2017). Most
individuals have normal intellect, although intellectual disability has
been reported
(Basart et al., 2015; Wade et al., 2016). In total, 19 FMD2 patients
carrying variants in MAP3K7 have been described in literature
(Wade et al., 2017; Costantini et al., 2018). A recurrent variant was
identified in 16 patients (c.1454C>T (p.Pro485Leu)), and
the other three described variants causing the FMD2 phenotype are
c.208G>C (p.Glu70Gln), c.299T>A (p.Val100Glu)
and c.502G>C (p.Gly168Arg). This recurrent variant leads to
a severe skeletal phenotype, keloid scarring, and (in 3 out of 16
patients) intellectual disability (ID). The three patients with the
infrequent missense variants show a milder phenotype consistent with
FMD, without ID (Costantini et al., 2018).
CSCF was first described in 1966 as a new syndrome and autosomal
dominant inheritance was suggested (Forney et al., 1966). The initial
report describes a mother and two of her four daughters with congenital
mitral valve insufficiency, skeletal malformations (fusion of cervical
vertebrae/tarsal bones/carpal bones, phalangeal shortening), conductive
deafness and short stature. The hearing loss resulted from fusion of the
stapes to the round window and was improved by surgical correction. In
2010, two additional patients with an overlapping phenotype were
reported introducing the name CSCF for the first time (Sousa et al.,
2010). However, it was not until 2016 that the gene MAP3K7 was
identified as the cause of CSCF by Le Goff et al.
(Le Goff et al., 2016) who described 6 patients with CSCF phenotype and
a causative heterozygous missense variant in the gene: three sporadic
cases and one family (a father and two sons). Morlino et al. summarize
these patients in their publication, adding a twelfth novel patient with
CSCF due to a de novo variant in the MAP3K7 gene
(Morlino et al., 2018). In 2020, the same group published functional
studies on patient fibroblasts demonstrating that CSCF is caused by
loss-of-function variants in the gene through the TGFβ-pathway (Micale
et al., 2020). Interestingly, intellectual disability (ID) has been
described in FMD2, but not in CSCF.
Here, we expand the cohort of individuals with CSCF and FMD2 carrying
variants in MAP3K7 , describing 14 novel patients with CSCF and 2
novel patients with FMD2 (one with the recurrent variant and severe ID).
Based on the phenotype of the patients we suggest that both CSCF and
FMD2 are connective tissue diseases. We describe severe congenital left
sided cardiac defects in CSCF patients and we hypothesize an overlap of
CSCF patients with the Noonan syndrome (NS) (OMIM 163950) phenotype.
Additionally, we provide for the first time a side-by-side comparison of
the biochemical effects of missense variants in MAP3K7 for CSCF
and FMD2, aiming to find a molecular fingerprint to distinguish between
the two disorders.