The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations

Geeske M. van Woerden*, Richelle Senden, Charlotte de Konink, Rossella A. Trezza, Anwar Baban, Jennifer A. Bassetti, Yolande van Bever, Lynne M. Bird, Bregje W. van Bon, Alice S. Brooks, Qiaoning Guan, Eric W. Klee, Carlo Marcelis, Joel M. Rosado, Lisa A. Schimmenti, Amy R. Shikany, Paulien A. Terhal, Kathryn Nicole Weaver, Marja W. Wessels, Hester van WieringenAnna C. Hurst, Catherine F. Gooch, Katharina Steindl, Pascal Joset, Anita Rauch, Marco Tartaglia, Marcello Niceta, Ype Elgersma, Serwet Demirdas

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)


Mitogen-activated protein 3 kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor β-activated kinase 1, which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to two distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF). The fact that different mutations can induce two 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 patients with CSCF and FMD2 who carry mutations in MAP3K7. Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease, and we show overlap in clinical phenotypes of CSCF with Noonan syndrome (NS). Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations 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 NS.

Original languageEnglish
Pages (from-to)1377-1395
Number of pages19
JournalHuman Mutation
Issue number10
Publication statusPublished - Oct 2022

Bibliographical note

The authors would like to thank patients for their willingness to share their information to further our understanding of cardiospondylocarpofacial syndrome and frontometaphyseal dysplasia type 2. They would also like to thank Dr. Ineke van der Burgt (Division of Human Genetics, Radboud Medical Center, Radboud University, Nijmegen, The Netherlands) for her valuable insights and help in setting up the study. Eric W. Klee, Joel M. Rosado, and Lisa A. Schimmenti are supported by the Center for Individualized Medicine, Mayo Clinic. Part of the work of Anwar Baban, Marcello Niceta, and Marco Tartaglia was supported by funding from the Italian Ministry of Health (CCR-2017-23669081, RCR-2020-23670068_001 to Marco Tartaglia) and Italian Ministry of Research (FOE 2019, 2020 Sviluppo di protocolli innovativi e applicazione di nuovi strumenti-omici nei pazienti orfani di diagnosi to Marco Tartaglia). Geeske M. van Woerden was funded by NWO-VIDI (016.Vidi.188.014)

Publisher Copyright: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.


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