The Y chromosome disomy syndrome (47, XYY) in children with mental retardation, deviations of sex development and different genome anomalies: molecular cytogenetic studies

The article present the results of retrospectively analyzed children (4424 boys) with mental and psychomotor retardation, congenital malformations and/or developmental micro anomalies. 23 children had various forms of Y chromosome dysomy syndrome. The frequency of this syndrome in the studied cohort was 0.52%; and in this connection the authors discussed the role of Y-chromosome in the origin of mental retardation. Besides, the chromosome instability in sex and somatic cells is supposed to be a common mechanism of different chromosomal anomalies. The authors discussed the possibility of cytogenetic and molecular cytogenetic diagnosis, and also clinical polymorphism of the syndrome. The authors established the necessity of molecular cytogenetic technologies in the diagnosis of different forms of the syndrome, including mosaic forms and isodicentric chromosomes-connected forms. The severity of clinical symptoms doesn’t depend on presence of regular or mosaic forms of the syndrome. The study assumes a possible connection of clinical polymorphism with mosaisism, associated with the presence of abnormal cells (cell lines) in different tissues, together with the role of Y chromosome in the origin of mental retardation in children with Y- chromosome disomy syndrome and other chromosomal anomalies. The authors underline the necessity of molecular cytogenetic diagnosis of different forms of the syndrome for correct medical and genetic consultation.

1. Ворсанова С.Г., Юров Ю.Б., Чернышов В.Н. Медицинская цитогенетика. М.: Медпрактика-М, 2006; 300. [Vorsanova S.G., Yurov Y.B., Chernyshov V.N. Medical cytogenetics. Moscow: Medpraktika-M, 2006; 300 (in Russ.)]

2. Fryns J.P., Kleczkowska A., Kubień E., Van Der Berghe H. XYY syndrome and other Y chromosome polysomies. Mental status and psychosocial functioning. Genet Couns 1995; 6(3): 197–206.

3. Parker C.E., Melyk J., Fish C.H. The XYY syndrome. Am J Med 1969; 47(5): 801–808.

4. Powell C.M. Sex Chromosomes, Sex Chromosome Disorders, and Disorders of Sex Development. The Principles of Clinical Cytogenetics. S.L. Gersen, M.B. Keagle (eds). Springer-Verlag New York, 2013; 175–211.

5. Hier D.B., Atkin L., Perlo V.P. Learning disorders and sex chromosome aberrations. J Ment Def Res 1980; 24(1): 17–26.

6. Gelisio P., Frigato F., Magnanini P., Saonato F., de Riva C., Virgili F. XYY syndrome. Report of a case. Minerva Endocrinol 1991; 16(4): 199–201.

7. Asano A., Motomura N., Yokota S., Yoneda H., Sakai T., Tsutsumi S. Myotonic dystrophy associated with 47,XYY syndrome. Psychiatry Clin Neurosci 2000; 54(1): 113–116.

8. Green T., Flash S., Reiss A.L. Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacol 2019; 44(1): 9–21. DOI: 10.1038/s41386-018-0253-2

9. Liao C., Fu F., Zhang L. Ring chromosome 13 syndrome characterized by high resolution array based comparative genomic hybridization in patient with 47, XYY syndrome: a case report. J Med Case Rep 2011; 5: 99. DOI: 10.1186/1752-1947-5-99.

10. Kolaitis G., Bouwkamp C.G., Papakonstantinou A., Otheiti I., Belivanaki M., Haritaki S. et al. A boy with conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), borderline intellectual disability, and 47,XYY syndrome in combination with a 7q11.23 duplication, 11p15.5 deletion, and 20q13.33 deletion. Child Adolesc Psychiatry Ment Health 2016; 10: 33. DOI: 10.1186/s13034-016-0121-8

11. Le Gall J., Nizon M., Pichon O., Andrieux L., Audebert-Bellanger S., Baron S. et al. Sex chromosome aneuploidies and copy-number variants: a further explanation for explanation for neurodevelopmental prognosis variability? Eur J Hum Genet 2017; 25(8): 930–934. DOI: 10.1038/ejhg.2017.93

12. Bishop D.V.M., Brookman-Byrne A., Gratton N., Gray E., Holt G., Morgan L. et al. Language phenotypes in children with sex chromosome trisomies. Version 2. Wellcome Open Res 2019; 3: 1434. DOI: 10.12688/well come openes.14904.2

13. Telfer M.A., Baker D., Clark G.R., Richardson C.E. Incidence of gross chromosomal errors among tall. American males. Science 1968; 159(3820): 1249–1250.

14. Des Groseillers M., Lemyre E., Dallaire L., Lemieux N. Tetrasomy Y by structural rearrangement: clinical report. Am J Med Genet 2002; 111(4): 401–404.

15. Schwanitz G., Hagner M. Double trisomy as a mosaic. Case history (48,XYY,+21/47,XY,+21) and survey of the literature of mixed autosomal-gonosomal trisomies. Acta Genenet Med Gemelol 1978; 27: 67–74.

16. Grass F., McCombs J., Scott C.I., Young R.S., Moore C.M. Reproduction in XYY males: two new cases and implications for genetic counseling. Am J Med Genet 1984; 19(3): 553–560. DOI: 10.1002/ajmg.1320190318

17. Stalker H.J., Keller K.L., Gray B.A., Zori R.T. Concurrence of fragile syndrome and 47,XYY in an individual with a Prader-Willie-like phenotype. Am J Med Genet A 2003; 116A(2): 176–178.

18. Dutra R.L., Piazzon F.B., Zanardo É.A., Costa T.V., Montenegro M.M., Novo-Filho G.M. et al. Rare genomic rearrangement in a boy with Willams-Beuren syndrome associated to XYY syndrome intriguing behavior. Am J Med Genet A 2015; 167A(12): 3197–3203. DOI: 10.1002/ajmg.a.37360

19. Milunsky A., Huang X., Amos J.A., Herskowitz J., Farrer L.A., Wyandt H.E. 46,XY/47,XYY male with the fragile X syndrome: cytogenetic and molecular studies. Am J Med Genet 1993; 45(5): 589–593.

20. Mutesa L., Jamar M., Hellin A.C., Pierquin G., Bours V. A new 48,XXYY/47,XYY syndrome associated with multiple skeletal abnormalities, congenital heart disease and mental retardation. Indian J Hum Genet 2012; 18(3): 352–355. DOI: 10.4103/0971-6866.108033

21. Soloviev I.V., Yurov Y.B., Vorsanova S.G., Malet P. Microwave activation of fluorescence in situ hybridization: a novel method for rapid chromosome detection and analysis. Focus 1994; 16(4): 115–116.

22. Юров И.Ю., Ворсанова С.Г., Саприна Е.А., Юров Ю.Б. Выявление генов-кандидатов аутизма, основанное на молекулярно-цитогенетическом и in silico анализах геномной организации хромосомных участков, вовлеченных в несбалансированные перестройки. Генетика 2010; 46(10): 1348– 1351. [Iourov I.Y., Vorsanova S.G., Saprina E.A., Yurov Y.B. Identification of candidate genes of autism on the basis of molecular cytogenetic and in silico studies of the genome organization of chromosomal regions involved in unbalanced rearrangements. Genetika 2010; 46(10): 1348–1351. (in Russ.)]

23. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Somatic cell genomics of brain disorders: a new opportunity to clarify genetic-environmental interactions. Cytogenet Genome Res 2013; 139(3): 181–188. DOI: 10.1159/000347053

24. Юров И.Ю., Ворсанова С.Г., Юров Ю.Б. Современные достижения в молекулярно-цитогенетической диагностике наследственных болезней (лекция). Клиническая лабораторная диагностика 2005; 11: 21–29. [Iourov I.Y., Vorsanova S.G., Yurov Y.B. Current advances in molecular cytogenetic diagnosis of hereditary diseases (lecture). Klinicheskaya laboratornaya diagnostika (Russian Clinical Laboratory Diagnostics) 2005; 11: 21–29. (in Russ.)]

25. Yurov Y.B., Soloviev I.V., Vorsanova S.G., Marcais B., Roizes G., Lewis R. High resolution fluorescence in situ hybridization using сyanine and fluorescеin dyes ultra-rapid chromosome detection by directly fluorescently ladeled alphoid DNA probes. Human Genet 1996; 97: 390–398.

26. ISCN 2013/ISCN 2016 – An international system for human cytogenetic nomenclature. L.S. Shaffer, J. McGowan-Jordan, M. Schmid (eds). S. Karger, Basel, 2016; 139.

27. Shah A.H., Manjunatha B.S., Bindayel N.A., Khoungangian R. Oral health management of a patient with 47,XYY syndrome. BMJ Case Rep 2013; pii: bcr2013010408. DOI: 10.1136/bcr2013-010408

28. Nguyen-Minh S., Buhrer C., Hubner C., Kaindl A.M. Is microcephaly a so-far unrecognized feature of XYY syndrome? Meta Gene 2014; 2: 160–163. DOI: 10.1016/j. mgene.2013.10.013

29. Monastirli A., Stephanou G., Georgiou S., Adrianopoulos C., Pasmatzi E., Chroni E. et al. Short stature, type E brachydactyly, exostoses, gynecomastia, and cryptorchidism in a patient with 47,XYY/45,X/46,XY mosaicism. Am J Med Sci 2005; 329(4): 2208–2210.

30. Lettiero T., Del Giudice E., Imperati F., Ciao A., Capalbo D., Salerno M. Hormonal and neuropsychological evaluation of two 47,XYY patients with pituitary abnormalities. Am J Med Genet Part A 2008; 146A: 397–400. DOI: 10.1002/ ajmg.a.32123

31. Iourov I.Y., Vorsanova S.G., Kurinnaia O.S., Zelenova M.A., Silvanovich A.P., Yurov Y.B. Molecular karyotyping by array CGH in a Russian cohort of children with intellectual disability, autism, epilepsy, and congenital anomalies. Molecular Cytogenetics 2012; 5(1):46. DOI: 10.1186/1755-8166-5-46

32. Iourov I.Y., Vorsanova S.G., Yurov Y.B. In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research. Molecular Cytogenetics 2014; 7(1):98. DOI: 10.1186/s13039-014-0098-z

33. Юров И.Ю., Ворсанова С.Г., Коростелев С.А., Васин К.С., Зеленова М.А., Куринная О.С., Юров Ю.Б. Структурные вариации генома при аутистических расстройствах с умственной отсталостью. Журнал неврологии и психиатрии им. C.C. Корсакова 2016; 116(7): 50–54. [Iourov I.Y., Vorsanova S.G., Korostelev S.A., Vasin K.S., Zelenova M.A., Kurinnaia O.S., Iourov Y.B. Structural variations of the genome in autistic spectrum disorders with intellectual disability. Zhurnal nevrologii i psihiatrii im. C.C. Korsakova 2016; 116(7): 50–54. (in Russ.)]

34. Iourov I.Y., Liehr T., Vorsanova S.G., Mendez-Rosado L.A., Yurov Y.B. The applicability of interphase chromosome-specific multicolor banding (ICS-MCB) for studying neurodevelopmental and neurodegenerative disorders. Res Results Biomed 2019; 5(3): 4–9. DOI:10.18413/2658-6533-20195-3-0-1

35. Ворсанова С.Г., Юров И.Ю., Куринная О.С., Воинова В.Ю., Юров Ю.Б. Геномные аномалии у детей с умственной отсталостью и аутизмом: использование технологии сравнительной геномной гибридизации на хромосомах in situ (HR CGH) и молекулярного кариотипирования на ДНК микроматрицах (array CGH). Журнал неврологии и психиатрии им. C.C. Корсакова 2013; 113(8): 46–49. [Vorsanova S.G., Iourov I.Y., Kurinnaia O.S., Voinova V.Yu., Yurov Y.B. Genomic abnormalities in children with mental retardation and autism: the use of comparative genomic hybridization in situ (HRCGH) and molecular karyotyping with DNA-microchips (array CGH). Zhurnal nevrologii i psihiatrii im. C.C. Korsakova 2013; 113(8): 46–49. (in Russ.)]

36. Yurov Y.B., Vorsanova S.G., Iourov I.Y. Ontogenetic variation of the human genome. Current Genomics 2010; 11(6): 420– 425. DOI: 10.21926/obm.genet.1902076