@article{5559a2d3acec4f01a3be2c92a4f9e804,
title = "The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations",
abstract = "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.",
keywords = "MAP3K7, Noonan syndrome, cardiospondylocarpofacial syndrome, frontometaphyseal dysplasia type 2",
author = "{van Woerden}, {Geeske M.} and Richelle Senden and {de Konink}, Charlotte and Trezza, {Rossella A.} and Anwar Baban and Bassetti, {Jennifer A.} and {van Bever}, Yolande and Bird, {Lynne M.} and {van Bon}, {Bregje W.} and Brooks, {Alice S.} and Qiaoning Guan and Klee, {Eric W.} and Carlo Marcelis and Rosado, {Joel M.} and Schimmenti, {Lisa A.} and Shikany, {Amy R.} and Terhal, {Paulien A.} and {Nicole Weaver}, Kathryn and Wessels, {Marja W.} and {van Wieringen}, Hester and Hurst, {Anna C.} and Gooch, {Catherine F.} and Katharina Steindl and Pascal Joset and Anita Rauch and Marco Tartaglia and Marcello Niceta and Ype Elgersma and Serwet Demirdas",
note = "Funding Information: 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) Funding Information: 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 to Marco Tartaglia). Geeske M. van Woerden was funded by NWO‐VIDI (016.Vidi.188.014) Sviluppo di protocolli innovativi e applicazione di nuovi strumenti‐omici nei pazienti orfani di diagnosi Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",
year = "2022",
month = oct,
doi = "10.1002/humu.24425",
language = "English",
volume = "43",
pages = "1377--1395",
journal = "Human Mutation",
issn = "1059-7794",
number = "10",
}