A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis

Hum Genet. 2020 Apr;139(4):461-472. doi: 10.1007/s00439-019-02102-9. Epub 2020 Jan 24.


SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Arachnodactyly* / diagnosis
  • Arachnodactyly* / genetics
  • Arachnodactyly* / metabolism
  • Child
  • Child, Preschool
  • Craniosynostoses* / diagnosis
  • Craniosynostoses* / genetics
  • Craniosynostoses* / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Humans
  • Male
  • Marfan Syndrome* / diagnosis
  • Marfan Syndrome* / genetics
  • Marfan Syndrome* / metabolism
  • Middle Aged
  • Mutation*
  • Pathology, Molecular
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • SKI protein, human

Supplementary concepts

  • Shprintzen Golberg craniosynostosis