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Mosaic variegated aneuploidy syndrome

Written2011-12Sandra Hanks, Katie Snape, Nazneen Rahman
Institute of Cancer Research, Division of Genetics, Epidemiology, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK

(Note : for Links provided by Atlas : click)


Other namesMVA
Atlas_Id 10167
Genes implicated inBUB1B   CEP57  
Inheritance Autosomal recessive; rare with unknown incidence.


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.
Treatment Clinical management of patients with MVA syndrome is based upon the affected individual's 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.
Prognosis 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 conditions 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.
  Figure 1. Examples of karyotypic abnormalities identified in individuals with MVA.
Cytogenetics of cancer 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

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

Genes involved and Proteins

Gene NameBUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast))
Alias BUBR1 Bub1A MAD3L SSK1
Location 15q15.1
Description BUB1B spans 60 kb and is composed of 23 exons.
Note Protein name: BUBR1
Description 1050 amino acids, 120 kDa.
Expression Ubiquituously expressed. Preferentially expressed in tissues with a high mitotic index.
Localisation Cytoplasmic in interphase cells. Bound to BUB3 or CENPE, it can be localised to nuclear kinetochores. BUBR1 also localises to centrosomes during interphase.
Function 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.
Homology BUBR1 is the mammalian homologue of yeast Mad3, a significant difference being that BUBR1 possesses a kinase domain which is absent in Mad3.
Germinal 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.

Gene NameCEP57 (centrosomal protein 57kDa)
Alias PIG8 TSP57 Translokin KIAA0092
Location 11q21
Description CEP57 spans over 42 kb and is composed of 11 exons.
Description 500 amino acids, 57 kDa.
Expression Ubiquituously expressed.
Localisation Nucleus, cytoplasm, cytoskeleton, centrosome.
Function Centrosomal protein required for microtubule attachment to centrosomes. Also involved in intracellular bidirectional trafficking of factors such as FGF2 along microtubules.
Homology The CEP57 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.
Germinal Biallelic, loss-of-function mutations have been found in three MVA pedigrees (figure 7).


Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.
Garcia-Castillo H, Vasquez-Velasquez AI, Rivera H, Barros-Nunez P.
Am J Med Genet A. 2008 Jul 1;146A(13):1687-95. (REVIEW)
PMID 18548531
Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.
Hanks S, Coleman K, Summersgill B, Messahel B, Williamson D, Pritchard-Jones K, Strefford J, Swansbury J, Plaja A, Shipley J, Rahman N.
Cancer Lett. 2006 Aug 8;239(2):234-8. Epub 2005 Sep 22.
PMID 16182441
BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells.
Izumi H, Matsumoto Y, Ikeuchi T, Saya H, Kajii T, Matsuura S.
Oncogene. 2009 Aug 6;28(31):2806-20. Epub 2009 Jun 8.
PMID 19503101
Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects.
Lane AH, Aijaz N, Galvin-Parton P, Lanman J, Mangano R, Wilson TA.
Am J Med Genet. 2002 Jul 1;110(3):273-7.
PMID 12116237
Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.
Limwongse C, Schwartz S, Bocian M, Robin NH.
Am J Med Genet. 1999 Jan 1;82(1):20-4. (REVIEW)
PMID 9916837
Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.
Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E, Tsutsui K, Kobayashi J, Tauchi H, Kajiwara Y, Hama S, Kurisu K, Tahara H, Oshimura M, Komatsu K, Ikeuchi T, Kajii T.
Am J Med Genet A. 2006 Feb 15;140(4):358-67.
PMID 16411201
Pivotal role of translokin/CEP57 in the unconventional secretion versus nuclear translocation of FGF2.
Meunier S, Navarro MG, Bossard C, Laurell H, Touriol C, Lacazette E, Prats H.
Traffic. 2009 Dec;10(12):1765-72. Epub 2009 Sep 14.
PMID 19804566
Cep57, a multidomain protein with unique microtubule and centrosomal localization domains.
Momotani K, Khromov AS, Miyake T, Stukenberg PT, Somlyo AV.
Biochem J. 2008 Jun 1;412(2):265-73.
PMID 18294141
The spindle-assembly checkpoint in space and time.
Musacchio A, Salmon ED.
Nat Rev Mol Cell Biol. 2007 May;8(5):379-93. Epub 2007 Apr 11. (REVIEW)
PMID 17426725
Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.
Snape K, Hanks S, Ruark E, Barros-Nunez P, Elliott A, Murray A, Lane AH, Shannon N, Callier P, Chitayat D, Clayton-Smith J, Fitzpatrick DR, Gisselsson D, Jacquemont S, Asakura-Hay K, Micale MA, Tolmie J, Turnpenny PD, Wright M, Douglas J, Rahman N.
Nat Genet. 2011 Jun;43(6):527-9. Epub 2011 May 8.
PMID 21552266
Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.
Suijkerbuijk SJ, van Osch MH, Bos FL, Hanks S, Rahman N, Kops GJ.
Cancer Res. 2010 Jun 15;70(12):4891-900. Epub 2010 Jun 1.
PMID 20516114


This paper should be referenced as such :
Hanks, S ; Snape, K ; Rahman, N
Mosaic variegated aneuploidy syndrome
Atlas Genet Cytogenet Oncol Haematol. 2012;16(5):376-380.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes CEP57

REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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