Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Shawn Yost, Bas de Wolf, Sandra Hanks, Anna Zachariou, Chiara Marcozzi, Matthew Clarke, Richarda M de Voer, Banafsheh Etemad, Esther Uijttewaal, Emma Ramsay, Harriet Wylie, Anna Elliott, Susan Picton, Audrey Smith, Sarah Smithson, Sheila Seal, Elise Ruark, Gunnar Houge, Jonathan Pines, Geert J P L KopsNazneen Rahman

Research output: Contribution to journal/periodicalArticleScientificpeer-review


Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis.

Original languageEnglish
Pages (from-to)1148-1151
Number of pages4
JournalNature Genetics
Issue number7
Publication statusPublished - Jul 2017


  • ATPases Associated with Diverse Cellular Activities
  • Aneuploidy
  • Carrier Proteins
  • Cell Cycle Proteins
  • Child, Preschool
  • Chromosome Segregation
  • DNA, Neoplasm
  • Developmental Disabilities
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Neoplasms
  • Leukemia, Myeloid, Acute
  • M Phase Cell Cycle Checkpoints
  • Microcephaly
  • Microtubule-Associated Proteins
  • Mosaicism
  • Mutation
  • Neoplasms, Multiple Primary
  • Nuclear Proteins
  • Ovarian Neoplasms
  • Protein-Serine-Threonine Kinases
  • RNA Stability
  • Seizures
  • Sertoli-Leydig Cell Tumor
  • Wilms Tumor
  • Journal Article


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