Medicine:Mosaic variegated aneuploidy syndrome

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Mosaic variegated aneuploidy syndrome is a rare autosomal recessive genetic disorder that causes inappropriate chromosomal segregation in mitosis process and because of it, some cells are aneuploid (mosaic).[1] It is caused by mutation BUB1, BUB1B, BUB3, CEP57 or TRIP13.[2][3][4][5]

Person with MVA can present with IUGR, microcephaly and a wide range of congenital abnormalities.[6]

Symptoms

Signs of this disease are:[7]

Very frequent:

  • Peritoneal fluid excess
  • Cataracts
  • Dandy-Walker malformation
  • Epicanthus
  • Glaucoma
  • Small jaw
  • increased nuchal translucency
  • Short stature
  • Enlargment of ventricles of the brain

Frequent:

  • Eye and vision abnormalities
  • Global developmental delay
  • Microcephaly
  • Mental handicap
  • Triangular facies

Occasional:

  • Anomalies of aortic morphology
  • Anomalies of cardiovascular system morphology
  • Lung lobation abnormality
  • Abnormalities of skull
  • Abnormality of immune system
  • Anomalies of skin pigmentation
  • Anomalies of the skeletal system
  • Atypical genitalia
  • Agenesis (or hypoplasia) of the cerebellum and the corpus callosum
  • Sleep apnea
  • Cleft palata
  • 5th finger clinodactyly
  • Tall forehead
  • Hypothyroidism
  • Wide nose
  • Sloping forehead
  • Some form of tumours, such as: Acute lymphoblastic leukemia, Nephroblastoma, Rhabdomyosarcoma, Wilms tumour etc.
  • Downslanted palpebral fissures
  • Depressed nasal ridge
  • Down-slanting palpebral fissures
  • IUGR (Intrauterine growth restriction)

Cause

This disorder is caused by defect of genes that are responsible for spindle checkpoint.[8]

Types include:

Genes that can cause MVA
Type OMIM Gene Locus
MVA1 257300 BUB1B 15q15.1
MVA2 614114 CEP57 11q21
MVA3 617598 TRIP13 5p15
MVA4 620153 CENATAC 11q23
MVA5 620184 SLF2 10q24
MVA6 620185 SMC5 9q21

Also those genes are associated with that disorder: BUB3 and BUB1.[9]

Pathophysiology

BUB1, BUB1B and BUB3 participates in spindle checkpoint checkpoint process which is necessary for correct chromosome splitting process in mitosis, consequently mutation of those 3 genes causes incorrect splitting of chromosomes.[10][11]

CENATAC gene is responsible for minor (U12‐dependent) spliceosome, which is important for cell cycle regulation proteins and in MVA, this process is deregulated.[12]

CEP57 plays role in spindle pole integrity, which mutation can cause incorrect segregation during mitosis.[13][14]

SLF2 and SMC5 are necessary for proper chromosomal segregation through centromeric and sister chromatid cohesion, consequently this mechanism is disrupted in this disease.[15]

TRIP13 also participates in spindle checkpoint process by activating MAD2 and that activates spindle checkpoint and mutations in TRIP13 can cause MVA .[16]

Diagnosis

MVA can be suspected by phenotype and confirmed by 1.karyotyping, and 2.genetic testing.[17][18]

  1. Karyotyping is a process, when person's chromosomes are getting isolated and ordered in numerical order, consequently it can be checked for any anomalies.[19]
  2. Genetic testing is a process when person's blood or other tissue gets inspected to determine changes in their genes.[20]

Prognosis

The prognosis of MVA syndrome depends on the types of malformation presented in the individual.[21]

History

The first mention of MVA was made by Rudd and colleagues in 1983, although Warburton and colleagues coined the name of MVA in 1991.[22][23]

Prevalence

The prevalence of that disorder is 1/1 000 000.[17]

References

  1. ↑ "Orphanet: Diseases". https://www.orpha.net/en/disease/gene/list/1052?mode=name. 
  2. ↑ "Entry - #257300 - MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 1; MVA1 - OMIM" (in en-us). https://omim.org/entry/257300. 
  3. ↑ "Entry - *607951 - CENTROSOMAL PROTEIN, 57-KD; CEP57 - OMIM" (in en-us). https://omim.org/entry/607951. 
  4. ↑ "Entry - #617598 - MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 3; MVA3 - OMIM" (in en-us). https://omim.org/entry/617598. 
  5. ↑ "Mosaic variegated aneuploidy syndrome 1 (Concept Id: C1850343) - MedGen - NCBI" (in en). https://www.ncbi.nlm.nih.gov/medgen/338026#:~:text=Definition,a%20situation%20known%20as%20aneuploidy.. 
  6. ↑ García-Castillo, Herbert; Vásquez-Velásquez, Ana Isabel; Rivera, Horacio; Barros-Núñez, Patricio (2008). "Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: Delineation of clinical subtypes" (in en). American Journal of Medical Genetics Part A 146A (13): 1687–1695. doi:10.1002/ajmg.a.32315. ISSN 1552-4833. PMID 18548531. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32315. 
  7. ↑ "Orphanet: Clinical signs and symptoms". https://www.orpha.net/en/disease/sign/1052. 
  8. ↑ Matsuura, Shinya; Ito, Emi; Tauchi, Hiroshi; Komatsu, Kenshi; Ikeuchi, Tatsuro; Kajii, Tadashi (2000-08-01). "Chromosomal Instability Syndrome of Total Premature Chromatid Separation with Mosaic Variegated Aneuploidy Is Defective in Mitotic-Spindle Checkpoint" (in English). The American Journal of Human Genetics 67 (2): 483–486. doi:10.1086/303022. ISSN 0002-9297. PMID 10877982. 
  9. ↑ Voer, Richarda M. de; Kessel, Ad Geurts van; Weren, Robbert D. A.; Ligtenberg, Marjolijn J. L.; Smeets, Dominique; Fu, Lei; Vreede, Lilian; Kamping, Eveline J. et al. (2013-09-01). "Germline Mutations in the Spindle Assembly Checkpoint Genes BUB1 and BUB3 Are Risk Factors for Colorectal Cancer" (in English). Gastroenterology 145 (3): 544–547. doi:10.1053/j.gastro.2013.06.001. ISSN 0016-5085. PMID 23747338. https://pubmed.ncbi.nlm.nih.gov/. 
  10. ↑ Bolanos-Garcia, Victor M.; Blundell, Tom L. (2011-03-01). "BUB1 and BUBR1: multifaceted kinases of the cell cycle". Trends in Biochemical Sciences 36 (3): 141–150. doi:10.1016/j.tibs.2010.08.004. ISSN 0968-0004. PMID 20888775. 
  11. ↑ Taylor, S. S.; Ha, E.; McKeon, F. (1998-07-13). "The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase". The Journal of Cell Biology 142 (1): 1–11. doi:10.1083/jcb.142.1.1. ISSN 0021-9525. PMID 9660858. 
  12. ↑ de Wolf, Bas; Oghabian, Ali; Akinyi, Maureen V; Hanks, Sandra; Tromer, Eelco C; van Hooff, Jolien J E; van Voorthuijsen, Lisa; van Rooijen, Laura E et al. (2021-07-15). "Chromosomal instability by mutations in the novel minor spliceosome component CENATAC". The EMBO Journal 40 (14). doi:10.15252/embj.2020106536. ISSN 0261-4189. PMID 34009673. 
  13. ↑ Snape, Katie; Hanks, Sandra; Ruark, Elise; Barros-Núñez, Patricio; Elliott, Anna; Murray, Anne; Lane, Andrew H.; Shannon, Nora et al. (June 2011). "Mutations in CEP57 cause mosaic variegated aneuploidy syndrome" (in en). Nature Genetics 43 (6): 527–529. doi:10.1038/ng.822. ISSN 1546-1718. PMID 21552266. 
  14. ↑ Wu, Qixi; He, Runsheng; Zhou, Haining; Yu, Albert CH; Zhang, Bo; Teng, Junlin; Chen, Jianguo (September 2012). "Cep57, a NEDD1-binding pericentriolar material component, is essential for spindle pole integrity" (in en). Cell Research 22 (9): 1390–1401. doi:10.1038/cr.2012.61. ISSN 1748-7838. PMID 22508265. 
  15. ↑ Grange, Laura J.; Reynolds, John J.; Ullah, Farid; Isidor, Bertrand; Shearer, Robert F.; Latypova, Xenia; Baxley, Ryan M.; Oliver, Antony W. et al. (2022-11-04). "Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy" (in en). Nature Communications 13 (1): 6664. doi:10.1038/s41467-022-34349-8. ISSN 2041-1723. PMID 36333305. Bibcode: 2022NatCo..13.6664G. 
  16. ↑ Kim, Dong Hyun; Han, Joo Seok; Ly, Peter; Ye, Qiaozhen; McMahon, Moira A.; Myung, Kyungjae; Corbett, Kevin D.; Cleveland, Don W. (2018-10-19). "TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC" (in en). Nature Communications 9 (1): 4354. doi:10.1038/s41467-018-06774-1. ISSN 2041-1723. PMID 30341343. Bibcode: 2018NatCo...9.4354K. 
  17. ↑ 17.0 17.1 Yamaguchi, Tomoko; Yamaguchi, Masatoshi; Akeno, Keiko; Fujisaki, Midori; Sumiyoshi, Kaeko; Ohashi, Masanao; Sameshima, Hiroshi; Ozaki, Mamoru et al. (2018). "Prenatal diagnosis of premature chromatid separation/mosaic variegated aneuploidy (PCS/MVA) syndrome" (in en). Journal of Obstetrics and Gynaecology Research 44 (7): 1313–1317. doi:10.1111/jog.13647. ISSN 1447-0756. PMID 29673003. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.13647. 
  18. ↑ Feng, Biyun; Chang, Guoying; Zhang, Qianwen; Li, Xin; Tang, Yijun; Gu, Shili; Wang, Yirou; Wang, Jian et al. (2022). "A novel CEP57 variant associated with mosaic variegated aneuploidy syndrome in a Chinese female presenting with short stature, microcephaly, brachydactyly, and small teeth" (in en). Molecular Genetics & Genomic Medicine 10 (6). doi:10.1002/mgg3.1951. ISSN 2324-9269. PMID 35434947. 
  19. ↑ "Karyotype" (in en). https://www.genome.gov/genetics-glossary/Karyotype. 
  20. ↑ Alliance, Genetic; Screening Services, The New York-Mid-Atlantic Consortium for Genetic and Newborn (2009-07-08), "GENETIC TESTING" (in en), Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals (Genetic Alliance), https://www.ncbi.nlm.nih.gov/books/NBK115571/, retrieved 2025-03-29 
  21. ↑ "Mosaic variegated aneuploidy syndrome". https://atlasgeneticsoncology.org/cancer-prone-disease/10167/mosaic-variegated-aneuploidy-syndrome. 
  22. ↑ Rudd, Noreen L.; Teshima, Iluko E.; Martin, Renee H.; Sisken, Jesse E.; Weksberg, Rosanna (1983-12-01). "A dominantly inherited cytogenetic anomaly: A possible cell division mutant" (in en). Human Genetics 65 (2): 117–121. doi:10.1007/BF00286646. ISSN 1432-1203. PMID 6654324. https://link.springer.com/article/10.1007/BF00286646. 
  23. ↑ Warburton, D.; Anyane-Yeboa, K.; Taterka, P.; Yu, C. Y.; Olsen, D. (1991). "Mosaic variegated aneuploidy with microcephaly: a new human mitotic mutant?". Annales de Génétique 34 (3–4): 287–292. ISSN 0003-3995. PMID 1809239. 



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