Klinefelter syndrome in a patient with double Y-autosomal translocation

   Klinefelter syndrome is one of the most common chromosomal abnormalities and the most common genetic cause of male infertility. About 85 % of patients have 47,XXY karyotype, other patients have other non-mosaic and mosaic Klinefelter syndrome variants. We report a unique clinical case — Klinefelter syndrome patient with double Y autosomal translocation. The proband is a 15-year-old male patient (height 180 cm, weight 50 kg, normal IQ) who was admitted for cytogenetic examination and genetic counseling due to delayed puberty. He was diagnosed with testicular hypoplasia, hypergonadotropic hypogonadism, pituitary microadenoma and left-sided varicocele. The proband was born in a nonconsanguineous marriage after in vitro fertilization due to paternal male factor infertility. Cytogenetic analysis was performed on cultured peripheral blood lymphocytes using standard chromosome analysis with GTG staining and FISH analysis. Molecular analysis of the Y chromosome was performed by multiplex PCR. Complex cytogenetic examination revealed a 46,XX,der(Y) t(Y;15)(q12;q11.1),der(13)t(Y;13)(q12;p11.2),-15 karyotype in the proband. Molecular analysis showed that the proband is SRY positive; no microdeletion of the Y chromosome was found. The detected double Y autosomal translocation is a chromosomal abnormality independent of KS. The father of the proband is an oligozoospermic man with robertsonian translocation 13;15 — 45,XY,der(13;15)(q10;q10), the mother has a normal karyotype 46,XX. Apparently, the der(13) and der(Y) chromosomes result from abnormal meiotic recombination in paternal meiosis between the heterochromatic region Yq12 and the centromeric/pericentromeric heterochromatin of chromosomes 13 and 15 involved in the paternal robertsonian translocation, and Klinefelter syndrome is due to the presence of two X chromosomes in the karyotype in the presence of a derivative Y chromosome. The detected double Y-autosomal translocation is a chromosomal abnormality unrelated to Klinefelter syndrome, arising on the background of the paternal robertsonian translocation.

1. Baranov V.S., Kuznetsova T.V. Cytogenetics of human embryonic development: scientific and practical aspects. 2006. St. Petersburg: Publishing House N-L, 2006; 640 p. (in Russ.)

2. Vorsanova S.G., Yurov Yu.B., Chernyshov V.N. Medicinskaya cytogenetika. Moscow: Medpraktika-M, 2006; 300. (in Russ.)

3. Gardner R.J.M., Amor D.J. Gardner and Sutherland’s Chromosome Abnormalities and Genetic Counseling. 5^th Edition, Oxford University Press, Oxford, 2018; 1268.

4. Medicinskaya genetika: nacional’noe rukovodstvo. Pod red. E.K. Gintera, V.P. Puzyreva, S.I. Kuceva. Moscow: GEOTAR-Media, 2022; 896. (in Russ.)

5. Berglund A., Stochholm K., Gravholt C.H. The epidemiology of sex chromosome abnormalities. Am J Med Genet C Semin Med Genet 2020; 184(2): 202–215. DOI: 10.1002/ajmg.c.31805

6. Chernykh V.B. Sex chromosomes abnormalities and CNVs, and their diagnosis. Medicinskaya genetika 2018; 17(10): 8–14. (in Russ.) URL: https://www.medgen-journal.ru/jour/article/view/586?locale=ru_RU

7. Shtaut M.I., Sorokina T.M., Kurilo L.F., Chernykh V.B. Spermatological characteristics of mosaic and non-mosaic forms of Klinefelter syndrome Andrologiya i genital’naya khirurgiya 2019; 20(4): 12–16. (in Russ.) URL: https://www.researchgate.net/publication/338067880_Shtaut_M_I_Sorokina_T_M_Kurilo_L_F_Chernykh_V_B_Spermatological_characteristics_of_mosaic_and_non-mosaic_forms_of_Klinefelter_syndrome_Andrologiya_i_genital'naya_khirurgiya_Andrology_and_Genital_Surge

8. Vorsanova S.G., Demidova I.A., Kolotii A.D., Kurinnaia O.S., Kravets V.S., Soloviev I.V. et al. Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis. Mol Cytogenet 2022; 15(1): 8. DOI: 10.1186/s13039–022–00588-z

9. Frühmesser A., Kotzot D. Chromosomal variants in Klinefelter syndrome. Sex Dev 2011; 5(3): 109–123. DOI: 10.1159/000327324

10. Lamy M., de Grouchy, Frezal J., Josso N., Feintuch G. Klinefelter’s syndrome and hypospadias. Presence of 2 X chromosomes. Rupture of Y chromosome and translocation of its fragments. C R Hebd Seances Acad Sci 1962; 255: 581–583.

11. Roberti M.C., La Starza R., Surace C., Sirleto P., Pinto R.M., Pierini V. et al. RABGAP1L gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome. Virchows Arch 2009; 454(3): 311–316. DOI: 10.1007/s00428–009–0732-z

12. Onrat S.T., Söylemez Z., Elmas M. 46,XX,der(15),t(Y;15) (q12;p11) karyotype in an azoospermic male. Indian J Hum Genet 2012; 18(2): 241–245. DOI: 10.4103/0971–6866.100785

13. ISCN 2020: An International System for Human Cytogenomic Nomenclature (2020). Editors J. McGowan-Jordan, R.J. Hastings, S Moore. Karger, 2020; 170. DOI: 10.1159/isbn.978–3–318–06867–2

14. Hsu L.Y. Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet 1994; 53: 108–140. DOI: 10.1002/ajmg.1320530204

15. Alitalo T., Tiihonen J., Hakola P., la Chapelle A. A Molecular characterization of a Y;15 translocation segregating in a family. Hum Genet 1988; 79: 29–35. DOI: 10.1007/BF00291705

16. Powell C. Sex chromosomes and sex abnormalities. The principles of clinical cytogenetics. Editors G.L. Gersen, M.B. Keagle. Totowa NJ: Humana Press; 1999; 229–258.

17. Manvelyan M., Riegel M., Santos M., Fuster C., Pellestor F., Mazaurik M.L. et al. Thirty-two new cases with small supernumerary marker chromosomes detected in connection with fertility problems: detailed molecular cytogenetic characterization and review of the literature. Int J Mol Med 2008; 21(6): 705–714.