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Involvement of MAP3K7 in FMD2 and CSCF, delineation of genotype/phenotype correlations.
  • +23
  • Geeske van Woerden,
  • Richelle Senden,
  • Charlotte de Konink,
  • Rossella Avagliano Trezza,
  • anwar baban,
  • Jennifer Bassetti,
  • Yolande Van Bever,
  • Lynne Bird,
  • Bregje van Bon,
  • Alice Brooks,
  • Qiaoning Guan,
  • Eric Klee,
  • Carlo Marcelis,
  • Joel Morales-Rosado,
  • Lisa Schimmenti,
  • Amy Shikany,
  • Paulien Terhal,
  • Kathryn Weaver,
  • Marja Wessels,
  • Hester van Wieringen,
  • Anna Hurst,
  • Catherine Gooch,
  • Marco Tartaglia,
  • Marcello Niceta,
  • Ype Elgersma,
  • Serwet Demirdas
Geeske van Woerden
Erasmus MC

Corresponding Author:[email protected]

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Richelle Senden
Erasmus MC
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Charlotte de Konink
Erasmus MC
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Rossella Avagliano Trezza
Erasmus MC
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anwar baban
Bambino Gesù Children's Hospital
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Jennifer Bassetti
Weill Cornell Medicine
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Yolande Van Bever
Erasmus MC
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Lynne Bird
UCSD
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Bregje van Bon
Nijmegen
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Alice Brooks
Erasmus MC
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Qiaoning Guan
Cincinnatti Children's Hospital Medical Center Division of Infectious Diseases
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Eric Klee
Mayo Clinic
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Carlo Marcelis
Radboudumc
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Joel Morales-Rosado
Mayo Clinic
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Lisa Schimmenti
Mayo Clinic
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Amy Shikany
Cincinnatti Children's Hospital Medical Center Division of Infectious Diseases
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Paulien Terhal
University Medical Center Utrecht
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Kathryn Weaver
Cincinnatti Children's Hospital Medical Center Division of Infectious Diseases
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Marja Wessels
Erasmus University Rotterdam
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Hester van Wieringen
Sint Antonius Hospital Surgery
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Anna Hurst
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Catherine Gooch
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Marco Tartaglia
Bambino Gesù Children’s Hospital, IRCCS
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Marcello Niceta
Bambino Gesù Children’s Hospital, IRCCS
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Ype Elgersma
Erasmus MC
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Serwet Demirdas
Erasmus MC
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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.
18 Oct 2021Submitted to Human Mutation
08 Nov 2021Submission Checks Completed
08 Nov 2021Assigned to Editor
20 Nov 2021Reviewer(s) Assigned
18 Dec 2021Review(s) Completed, Editorial Evaluation Pending
31 Dec 2021Editorial Decision: Revise Major
17 Mar 20221st Revision Received
05 Apr 2022Submission Checks Completed
05 Apr 2022Assigned to Editor
03 May 2022Reviewer(s) Assigned
18 May 2022Review(s) Completed, Editorial Evaluation Pending
02 Jun 2022Editorial Decision: Revise Minor
16 Jun 20222nd Revision Received
17 Jun 2022Submission Checks Completed
17 Jun 2022Assigned to Editor
17 Jun 2022Review(s) Completed, Editorial Evaluation Pending
20 Jun 2022Editorial Decision: Accept