A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder

Silvia Morlino, Marco Castori, Chiara Dordoni, Valeria Cinquina, Graziano Santoro, Paola Grammatico, Marina Venturini, Marina Colombi, Marco Ritelli

Research output: Contribution to journalArticlepeer-review

Abstract

Heterozygous variants in MAP3K7, encoding the transforming growth factor-β-activated kinase 1 (TAK1), are associated with the ultrarare cardiospondylocarpofacial syndrome (CSCFS). Specific gain-of-function variants in the same gene cause the allelic frontometaphyseal dysplasia type 2. Phenotypic series of frontometaphyseal dysplasia also comprise variants in FLNA (type 1) and two patients with a heterozygous variant in TAB2 (type 3). We report on a 7-year-old girl with CSCFS due to the novel heterozygous c.737-7A>G variant in MAP3K7. The identified variant generates a new splice acceptor site causing an in-frame insertion of 2 amino acid residues (p.Asn245_Gly246insValVal), as demonstrated by RNA study. The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility. Our study confirms locus homogeneity for CSCFS, expands the mutational spectrum of MAP3K7, and adds data on the existence of a community of connective tissue disorders caused by abnormalities of the TAK1-dependent signaling pathway.

Original languageEnglish
Pages (from-to)1-5
Number of pages5
JournalEuropean Journal of Human Genetics
DOIs
Publication statusAccepted/In press - Feb 21 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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