Mosaic Variegated Aneuploidy Syndrome 3

A number sign (#) is used with this entry because of evidence that mosaic variegated aneuploidy syndrome-3 (MVA3; 617598) is caused by homozygous mutation in the TRIP13 gene (604507) on chromosome 5p15.

Description

MVA3 is an autosomal recessive disorder resulting from errors in chromosome segregation. Most affected individuals develop early-onset Wilms tumor and show either aneuploidy or premature chromatid separation in cells. Some patients may have additional developmental features, such as microcephaly, growth retardation, or developmental delay (summary by Yost et al., 2017).

For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).

Clinical Features

Yost et al. (2017) reported 6 probands with onset of Wilms tumor in early childhood. Five of the patients were of Asian or Pakistani origin, and 4 of these families were consanguineous. The sixth patient was of Norwegian descent. Four of the patients had evidence of aneuploidy and/or premature chromatid separation in lymphocytes. Most patients had additional, but highly variable, features. The most severely affected child had microcephaly, severe global developmental delay, arthrogryposis, cone-rod dystrophy, nystagmus, and dysmorphic features. Brain imaging showed cerebral cysts and neuronal migration defects. In contrast, the least severely affected individual had only Wilms tumor and short stature, and was alive at age 43 years with no reported neurologic abnormalities. Two of the other patients had microcephaly and seizures, one of whom had developmental delay. Rare findings in the patients included growth retardation and pigmentary abnormalities of the skin. One patient had a sister who died at age 4 years from a Sertoli-Leydig cell tumor of the ovary and acute myeloid leukemia, but samples from this patient were not available.

Inheritance

The transmission pattern of MVA3 in the families reported by Yost et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 unrelated patients with MVA3, manifest as early-onset Wilms tumor, Yost et al. (2017) identified homozygous truncating mutations in the TRIP13 gene (604507.0001-604507.0002). Mutations in the first 3 patients were found by exome sequencing of 43 individuals from 20 families, including 21 probands with MVA. All 3 patients had Wilms tumor. Subsequent exome sequencing of 11 patients of Asian descent with Wilms tumor identified 2 additional patients with the same mutation (R354X; 604507.0001). All of the patients were of Asian or Pakistani descent, and the mutation segregated in all families from which parental DNA was available. The second mutation (604507.0002) was found in a 2.5-year-old girl of Norwegian descent with Wilms tumor; however, mosaic aneuploidy was not observed in her lymphocytes. Cells derived from patients with the R354X mutation showed chromosomal instability, including aneuploidy, premature chromatid separation, lagging chromosomes, and chromosome bridges. Mutant cells showed increased mitotic exit and impaired recruitment of MAD2 (see 601467) to unattached kinetochores, indicating severe disruption of the spindle assembly checkpoint. These defects could be restored with wildtype TRIP13. The mutant protein was unable to rescue spindle assembly checkpoint defects in a cell line with CRISPR-Cas9-mediated knockdown of TRIP13, consistent with a loss of function. The findings suggested that TRIP13 is a cancer predisposition gene.