Mosaic variegated aneuploidy syndrome

2011-12-01   Sandra Hanks , Katie Snape , Nazneen Rahman 

Institute of Cancer Research, Division of Genetics, Epidemiology, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK



Mosaic variegated aneuploidy syndrome




Autosomal recessive; rare with unknown incidence.


257300 , 614114




1052 Mosaic variegated aneuploidy syndrome




Phenotype and clinics

A broad spectrum of clinical features has been observed in individuals with MVA syndrome. Microcephaly, pre- and\/or postnatal growth retardation, variable developmental delay and dysmorphic facial features are frequently described. Seizures and other neurological abnormalities, eye anomalies including cataracts and strabismus, skeletal\/hand and foot abnormalities including clinodactyly and dermatological anomalies such as café au lait patches and haemangioma have also been described. Less common abnormalities include gastrointestinal defects, renal anomalies and cardiac defects. The clinical spectrum ranges from a severe and even lethal course to a mild phenotype without microcephaly or mental retardation.

Neoplastic risk

The risk of malignancy in MVA is high with Wilms tumour, rhabdomyosarcoma, leukaemia and granulosa cell tumour of the ovary reported in several cases. Myelodysplastic syndrome has also been observed.


Clinical management of patients with MVA syndrome is based upon the affected individuals specific needs and may include surgical treatments and intervention and\/or special education if developmental delay is detected. Standard treatment for specific neurological, ophthalmological, cardiac or renal anomalies may also be indicated. Due to the increased cancer risk, cases with a diagnosis of MVA syndrome should be offered Wilms tumour surveillance. Current UK recommendations include renal ultrasonography every three to four months until five years. There is no particular screening that is helpful for the other tumours known to be associated with MVA syndrome, but any suspicious clinical symptoms should be investigated with minimal delay.


The prognosis for an individual with MVA syndrome is based on the malformations present in the individual. There is early mortality in a significant proportion of cases due to failure to thrive and\/or complications of congenital abnormalities, epilepsy, infections or malignancy.


Inborn condition

MVA is characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues (examples are shown in figure 1). The proportion of aneuploid cells varies but is usually >10% and is substantially greater than in normal individuals. Some patients with MVA also demonstrate premature chromatid separation in colchicine-treated blood lymphocyte and fibroblast cultures.
Atlas Image
Figure 1. Examples of karyotypic abnormalities identified in individuals with MVA.

Cancer cytog

Gain of chromosomes 8 and 13 and loss of chromosomes 9 and 14 have been observed in the embryonal rhabdomyosarcoma from an individual with MVA. Gain of chromosome 8 has also been identified in the embryonal rhabdomyosarcoma from a further patient with MVA syndrome.

Other Findings


Cells from BUB1B mutation-positive cases demonstrate an abnormal response to nocodazole-induced mitotic checkpoint activation.

Genes involved and Proteins


Atlas Image
Figure 2. Schematic representation of BUB1B demonstrating the relative exon sizes.


BUB1B spans 60 kb and is composed of 23 exons.


Protein name: BUBR1
Atlas Image
Figure 3. Schematic representation of BUBR1 demonstrating significant functional or structural domains.


1050 amino acids, 120 kDa.


Ubiquituously expressed. Preferentially expressed in tissues with a high mitotic index.


Cytoplasmic in interphase cells. Bound to BUB3 or CENPE, it can be localised to nuclear kinetochores. BUBR1 also localises to centrosomes during interphase.


A central component of the mitotic spindle checkpoint that directly inhibits the anaphase-promoting complex\/cyclosome until sister chromatids are correctly attached to the spindle, thus ensuring proper chromosome segregation during cell division. Also binds the motor protein CENPE, an interaction required for regulation of kinetochore-microtubule interactions and checkpoint signalling.


BUBR1 is the mammalian homologue of yeast Mad3, a significant difference being that BUBR1 possesses a kinase domain which is absent in Mad3.
Atlas Image
Figure 4. Schematic representation of BUB1B demonstrating the relative exon sizes and positions of known mutations. Truncating mutations are depicted above the figure, with missense mutations below. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours. Monoallelic mutations are represented by black lines and font.


Biallelic germline mutations have been found in eight MVA pedigrees (figure 4). Each family carries one missense mutation and one mutation that results in premature protein truncation or an absent transcript. Monoalleic truncating mutations have also been reported in several cases.


Atlas Image
Figure 5. Schematic representation of CEP57 demonstrating the relative exon sizes.


CEP57 spans over 42 kb and is composed of 11 exons.
Atlas Image
Figure 6. Schematic representation of CEP57 demonstrating significant functional or structural domains.


500 amino acids, 57 kDa.


Ubiquituously expressed.


Nucleus, cytoplasm, cytoskeleton, centrosome.


Centrosomal protein required for microtubule attachment to centrosomes. Also involved in intracellular bidirectional trafficking of factors such as FGF2 along microtubules.


The CEP57 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.
Atlas Image
Figure 7. Schematic representation of CEP57 demonstrating the relative exon sizes and positions of known mutations. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours.


Biallelic, loss-of-function mutations have been found in three MVA pedigrees (figure 7).


Pubmed IDLast YearTitleAuthors
185485312008Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.García-Castillo H et al
161824412006Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.Hanks S et al
195031012009BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells.Izumi H et al
121162372002Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects.Lane AH et al
99168371999Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.Limwongse C et al
164112012006Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.Matsuura S et al
198045662009Pivotal role of translokin/CEP57 in the unconventional secretion versus nuclear translocation of FGF2.Meunier S et al
182941412008Cep57, a multidomain protein with unique microtubule and centrosomal localization domains.Momotani K et al
174267252007The spindle-assembly checkpoint in space and time.Musacchio A et al
215522662011Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.Snape K et al
205161142010Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.Suijkerbuijk SJ et al