In-frame mutations in exon 1 of SKI cause dominant shprintzen-goldberg syndrome

Virginie Carmignac, Julien Thevenon, Lesley Adès, Bert Callewaert, Sophie Julia, Christel Thauvin-Robinet, Lucie Gueneau, Jean Benoit Courcet, Estelle Lopez, Katherine Holman, Marjolijn Renard, Henri Plauchu, Ghislaine Plessis, Julie De Backer, Anne Child, Gavin Arno, Laurence Duplomb, Patrick Callier, Bernard Aral, Pierre VabresNadège Gigot, Eloisa Arbustini, Maurizia Grasso, Peter N. Robinson, Cyril Goizet, Clarisse Baumann, Maja Di Rocco, Jaime Sanchez Del Pozo, Frédéric Huet, Guillaume Jondeau, Gwenaëlle Collod-Beroud, Christophe Beroud, Jeanne Amiel, Valérie Cormier-Daire, Jean Baptiste Rivière, Catherine Boileau, Anne De Paepe, Laurence Faivre

Research output: Contribution to journalArticlepeer-review


Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.

Original languageEnglish
Pages (from-to)950-957
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - Nov 2 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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