Clinical, cytogenetic, and molecular findings of isodicentric Y chromosomes

Yang Yang1, Wang Hao1,2
1Prenatal Diagnosis Center, Hangzhou Maternity and Child Care Hospital, Hangzhou, China
2Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Hangzhou, China

Tóm tắt

Isodicentric Y chromosomes [idic(Y)] are one of the most common structural abnormalities of the Y chromosome. The prenatal diagnosis of isodicentric Y chromosomes is of vital importance, and the postnatal phenotypes vary widely. Therefore, we present six patients prenatally diagnosed with isodicentric Y chromosomes and review the literature concerning the genotype-phenotype correlations. The clinical materials of six patients were obtained. Cytogenetic and molecular approaches were carried out for these six patients. Isodicentric Y chromosomes were found in all sixpatients. Among them, four patients presented with a mosaic 45,X karyotype, one patient had a 46,XY cell line, and one patient was nonmosaic. Five of these six isodicentric Y chromosomes had a breakpoint in Yq11.2, and the other had a breakpoint in Yp11.3. The molecular analysis demonstrated different duplications and deletions of the Y chromosome. Finally, three patients chose to terminate the pregnancy, two patients gave birth to normal-appearing males, and one patient was lost to follow-up. The incorporation of multiple cytogenetic and molecular techniques would offer a more comprehensive understanding of this structural chromosomal abnormality for genetic counselling.

Từ khóa


Tài liệu tham khảo

Jacobs PA, Ross A. Structural abnormalities of the Y chromosome in man. Nature. 1966;210(5034):352–4. Hsu LY. Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet. 1994;53(2):108–40. Pasantes JJ, Wimmer R, Knebel S, Munch C, Kelbova C, Junge A, et al. 47,X,idic(Y),inv dup(Y): a non-mosaic case of a phenotypically normal boy with two different Y isochromosomes and neocentromere formation. Cytogenet Genome Res. 2012;136(2):157–62. Robinson DO, Dalton P, Jacobs PA, Mosse K, Power MM, Skuse DH, et al. A molecular and FISH analysis of structurally abnormal Y chromosomes in patients with turner syndrome. J Med Genet. 1999;36(4):279–84. Bergeron MB, Brochu P, Lemyre E, Lemieux N. Correlation of intercentromeric distance, mosaicism, and sexual phenotype: molecular localization of breakpoints in isodicentric Y chromosomes. Am J Med Genet A. 2011;155(11):2705–12. Stankiewicz P, Helias-Rodzewicz Z, Jakubow-Durska K, Bocian E, Obersztyn E, Rappold GA, et al. Cytogenetic and molecular characterization of two isodicentric Y chromosomes. Am J Med Genet. 2001;101(1):20–5. DesGroseilliers M, Beaulieu Bergeron M, Brochu P, Lemyre E, Lemieux N. Phenotypic variability in isodicentric Y patients: study of nine cases. Clin Genet. 2006;70(2):145–50. Bagci G, Acar H, Tomruk H. Different chromosome Y abnormalities in Turner syndrome. Genet Couns. 2001;12(3):255–61. Bettio D, Venci A, Rizzi N, Negri L, Setti PL. Clinical and molecular cytogenetic studies in three infertile patients with mosaic rearranged Y chromosomes. Hum Reprod. 2006;21(4):972–5. Pascual J, McMann LP, Gallagher T, Pinsker JE. Ambiguous genitalia in a newborn with 45,X/46,X,idic(Y) ovotesticular disorder of sex development. Endocr Pract. 2009;15(7):732–6. Kaprova-Pleskacova J, Snajderova M, Stoop J, Koudova M, Kocarek E, Novotna D, et al. 45,X/46,X,psu dic(Y) gonadal dysgenesis: influence of the two cell lines on the clinical phenotype, including gonadal histology. Sex Dev. 2013;7(6):282–8. Giltay JC, Ausems MG, van Seumeren I, Zewald RA, Sinke RJ, Faas B, et al. Short stature as the only presenting feature in a patient with an isodicentric (Y)(q11.23) and gonadoblastoma. A clinical and molecular cytogenetic study. Eur J Pediatr. 2001;160(3):154–8. Tuck-Muller CM, Chen H, Martinez JE, Shen CC, Li S, Kusyk C, et al. Isodicentric Y chromosome: cytogenetic, molecular and clinical studies and review of the literature. Hum Genet. 1995;96(1):119–29. Teraoka M, Narahara K, Yokoyama Y, Tsuji K, Kikkawa K, Ito S, et al. 45,X/46,X,idic(Yq) mosaicism: clinical, cytogenetic, and molecular studies in four individuals. Am J Med Genet. 1998;78(5):424–8. Speleman F, Van der Auwera B, Mangelschots K, Vercruyssen M, Raap T, Wiegant J, et al. Identification and characterization of normal length nonfluorescent Y chromosomes: cytogenetic analysis, southern hybridization and non-isotopic in situ hybridization. Hum Genet. 1990;85(6):569–75. Castro A, Rodriguez F, Florez M, Lopez P, Curotto B, Martinez D, et al. Pseudoautosomal abnormalities in terminal AZFb+c deletions are associated with isochromosomes Yp and may lead to abnormal growth and neuropsychiatric function. Hum Reprod. 2017;32(2):465–75. Lin SY, Lee CN, Peng AY, Yuan TJ, Lee DJ, Lin WH, et al. Application of molecular cytogenetic techniques to characterize the aberrant Y chromosome arising de novo in a male fetus with mosaic 45,X and solve the discrepancy between karyotyping, chromosome microarray, and multiplex ligation dependent probe amplification. J Formos Med Assoc. 2018;117(11):1027–31. Wu HH, Lee TH, Chen CD, Yeh KT, Chen M. Delineation of an isodicentric Y chromosome in a mosaic 45,X/46,X,idic(Y)(qter-p11.3::p11.3-qter) fetus by SRY sequencing, G-banding, FISH, SKY and study of distribution in different tissues. J Formos Med Assoc. 2007;106(5):403–10. Liu Y, Guo L, Chen H, Lu J, Hu J, Li X, et al. Discrepancy of QF-PCR, CMA and karyotyping on a de novo case of mosaic isodicentric Y chromosomes. Molecular Cytogenet. 2019;12:1. Liehr T, Klein E, Mrasek K, Kosyakova N, Guilherme RS, Aust N, et al. Clinical impact of somatic mosaicism in cases with small supernumerary marker chromosomes. Cytogenet Genome Res. 2013;139(3):158–63. Al-Rikabi ABH, Pekova S, Fan X, Jancuskova T, Liehr T. Small supernumerary marker chromosome may provide information on dosage-insensitive Pericentric regions in human. Curr Genomics. 2018;19(3):192–9. Lange J, Skaletsky H, van Daalen SK, Embry SL, Korver CM, Brown LG, et al. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell. 2009;138(5):855–69. Kuan LC, Su MT, Chen M, Kuo PL, Kuo TC. A non-mosaic isodicentric Y chromosome resulting from breakage and fusion at the Yq pseudo-autosomal region in a fetus. J Assist Reprod Genet. 2013;30(12):1559–62. Daniel A, Lyons N, Casey JH, Gras L. Two dicentric Y isochromosomes, one without and the Yqh heterochromatic segment: review of the Y isochromosomes. Hum Genet. 1980;54(1):31–9. Bruyere H, Speevak MD, Winsor EJ, de Freminville B, Farrell SA, McGowan-Jordan J, et al. IsodicentricYp: prenatal diagnosis and outcome in 12 cases. Prenat Diagn. 2006;26(4):324–9. Soares H, Maia A, Campos M, Doria S, Lopes JM, Fontoura M. Clinicopathological features of 45,X/46,Xidic(Y) mosaicism and therapeutic implications: case report. Sao Paulo Med J. 2008;126(5):297–9. Willis MJ, Bird LM, Dell’aquilla M, Jones MC. Natural history of prenatally diagnosed 46,X,isodicentric Y. Prenat Diagn. 2006;26(2):134–7. Tran CN, Semins MJ, Epstein JI, Gearhart JP. Ovotesticular disorder of sex development with mosaic 45,X/46,X,idic(Y) (q11.23) karyotype and streak gonad. Urology. 2011;78(5):1178–81. Neas KR, Yip MY, James C, Kirk EP. Patient with a non-mosaic isodicentricYp and mild developmental delay. Am J Med Genet A. 2005;137(2):223–4. Dundar M, Lowther G, Acar H, Kurtoglu S, Demiryilmaz F, Kucukaydin M. A case of ambiguous genitalia presenting with a 45,X/46,Xr(Y)(p11.2;q11.23)/47,X,idic(Y)(p11.2),idic(Y)(p11.2) karyotype. Ann Genet. 2001;44(1):5–8. Tomomasa H, Ogawa K, Nagasawa J, Satoh S, Muramatsu H, Iiyama T, et al. A case of mosaic Klinefelter syndrome associated with isodicentricYp. Reprod Med Biol. 2008;7(4):177–80. Iourov IY, Vorsanova SG, Liehr T, Monakhov VV, Soloviev IV, Yurov YB. Dynamic mosaicism manifesting as loss, gain and rearrangement of an isodicentric Y chromosome in a male child with growth retardation and abnormal external genitalia. Cytogenet Genome Res. 2008;121(3–4):302–6. Guevarra FM, Nimkarn S, New MI, Lin-Su K. Long-term growth hormone therapy in an adolescent boy with 45,X/46,XidicY(p11). The Journal of pediatrics. 2009;155(5):752–5. Gole LA, Anandakumar C, Yang R, Chan J, Wong YC, Bongso A. Discrepancy between cytogenetic and FISH results on an amniotic fluid sample of 45,X/46,X,idic(Y)(p11). Fetal Diagn Ther. 2000;15(4):212–5. Atkins KE, Gregg A, Spikes AS, Bacino CA, Bejjani BA, Kirkland J, et al. Identification of Y chromatin directly in gonadal tissue by fluorescence in situ hybridization (FISH): significance for Ullrich-turner syndrome screening in the cytogenetics laboratory. Am J Med Genet. 2000;91(5):377–82. Xu J, Siu VM. Is there a correlation between the proportion of cells with isodicentricYp at amniocentesis and phenotypic sex? Prenat Diagn. 2010;30(9):839–44. Hernando C, Carrera M, Ribas I, Parear N, Baraibar R, Egocue J, et al. Prenatal and postnatal characterization of Y chromosome structural anomalies by molecular cytogenetic analysis. Prenat Diagn. 2002;22(9):802–5. Bernstein R, Steinhaus KA, Cain MJ. Prenatal application of fluorescent in situ hybridization (FISH) for identification of a mosaic Y-chromosome marker, idic(Yp). Prenat Diagn. 1992;12(9):709–16. Huang B, Thangavelu M, Bhatt S, Sandlin C, Wang S. Prenatal diagnosis of 45,X and 45,X mosaicism: the need for thorough cytogenetic and clinical evaluations. Prenat Diagn. 2002;22(2):105–10. Roland B, Cox DM, Rudd NL. Sex chromosome mosaicism not detected at amniocentesis. Prenat Diagn. 1990;10(5):333–6. Marcus-Soekarman D, Hamers G, Mulder AL, Offermans J, Offermans J, Engelen J, et al. Sonographic genital ambiguity in a fetus due to a mosaic 45,X/46,X,idic(Y)(qter-p11.32::p11.32-qter) karyotype. Prenat Diagn. 2005;25(4):279–82. Liehr T, Mrasek K, Hinreiner S, Reich D, Ewers E, Bartels I, et al. Small supernumerary marker chromosomes (sSMC) in patients with a 45,X/46,X,+mar karyotype - 17 new cases and a review of the literature. Sex Dev. 2007;1(6):353–62. Raff R, Schubert R, Schwanitz G, van der Ven K, Bruhl P. Combination of hypospadias and maldescended testis as cardinal symptoms in gonosomal chromosome aberrations. Eur J Pediatr Surg. 2000;10(4):270–5. Guedes AD, Bianco B, Lipay MV, Brunoni D, de Lourdes Chauffaille M, Verreschi IT. Determination of the sexual phenotype in a child with 45,X/46,X,Idic(Yp) mosaicism: importance of the relative proportion of the 45,X line in gonadal tissue. Am J Med Genet A. 2006;140A(17):1871–5. Álvarez-Nava F, Soto M, Martínez MC, Prieto M, Álvarez Z. FISH and PCR analyses in three patients with 45,X/46,X,idic(Y) karyotype: clinical and pathologic spectrum. Ann Genet. 2003;46(4):443–8. Lukusa T, Fryns JP. Human chromosome fragility. Biochim Biophys Acta. 2008;1779(1):3–16. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346(6281):240–4. Aktas D, Alikasifoglu M, Gonc N, Senocak ME, Tuncbilek E. Isodicentric Y (p11.32) chromosome in an infant with mixed gonadal dysgenesis. Eur J Med Genet. 2006;49(2):141–9. Codina-Pascual M, Oliver-Bonet M, Navarro J, Starke H, Liehr T, Gutierrez-Mateo C, et al. FISH characterization of a dicentric Yq (p11.32) isochromosome in an azoospermic male. Am J Med Genet A. 2004;127A(3):302–6. Cui YX, Wang WP, Li TF, Li WW, Wu QY, Li N, et al. Clinical and cytogenomic studies in a case of infertility associated with a nonmosaic dicentric Y chromosome. Andrologia. 2015;47(4):477–81. Mekkawy M, Kamel A, El-Ruby M, Mohamed A, Essawi M, Soliman H, et al. Isodicentric Y chromosomes in Egyptian patients with disorders of sex development (DSD). Am J Med Genet A. 2012;158A(7):1594–603. Vogt PH, Edelmann A, Hirschmann P, Kohler MR. The azoospermia factor (AZF) of the human Y chromosome in Yq11: function and analysis in spermatogenesis. Reprod Fertil Dev. 1995;7(4):685–93. Valetto A, Bertini V, Rapalini E, Baldinotti F, Di Martino D, Simi P. Molecular and cytogenetic characterization of a structural rearrangement of the Y chromosome in an azoospermic man. Fertil Steril. 2004;81(5):1388–90. Jiang Y, Wang R, Li L, Xue L, Deng S, Liu R. Molecularcytogenetic study of de novo mosaic karyotype 45,X/46,X,i(Yq)/46,X,idic(Yq) in an azoospermic male: Case report and literature review. Mol Med Rep. 2017;16(3):3433–8. Ekici C, Esener Z, Korkmaz S, Salturk N, Yuksel S, Koc A. A Rare Mosaic Karyotype of 45,X/46,X,psu idic(Y)(p11.32)/46,XY with SHOX Haploinsufficiency, External Male Genitalia, and Short Stature. Sex Dev. 2019;13(1):41–6. Al-Achkar W, Wafa A, Liehr T, Klein E, Moassass F. Detailed analysis of an idic(Y)(q11.21) in a mosaic karyotype. Mol Med Rep. 2012;6(2):293–6. Heinritz W, Kotzot D, Heinze S, Kujat A, Kleemann WJ, Froster UG. Molecular and cytogenetic characterization of a non-mosaic isodicentric Y chromosome in a patient with Klinefelter syndrome. Am J Med Genet A. 2005;132A(2):198–201. Yoshitsugu K, Meerabux JM, Asai K, Yoshikawa T. Fine mapping of an isodicentric Y chromosomal breakpoint from a schizophrenic patient. Am J Med Genet B Neuropsychiatr Genet. 2003;116B(1):27–31. Mizuguchi T, Hashimoto R, Itokawa M, Sano A, Shimokawa O, Yoshimura Y, et al. Microarray comparative genomic hybridization analysis of 59 patients with schizophrenia. J Hum Genet. 2008;53(10):914–9. Jagannath AD, Rastogi U, Spooner AE, Lin AE, Agnihotri AK. Aortic dissection and moyamoya disease in Turner syndrome. Am J Med Genet A. 2010;152a(8):2085–9. BouayedAbdelmoula N, Abdelmoula B, Smaoui W, Trabelsi I, Louati R, Aloulou S, et al. Left-sided congenital heart lesions in mosaic turner syndrome. Mol Gen Genomics. 2017;293(2):495–501. Hipp LE, Mohnach LH, Wei S, Thomas IH, Elhassan ME, Sandberg DE, et al. Isodicentric Y mosaicism involving a 46, XX cell line: implications for management. Am J Med Genet A. 2016;170A(1):233–8. Fujimoto A, Boelter WD, Sparkes RS, Lin MS, Battersby K. Monozygotic twins of discordant sex both with 45,X/46,X,idic(Y) mosaicism. Am J Med Genet. 1991;41(2):239–45. Nonomura K, Kakizaki H, Fukuzawa N, Fujieda K, Harada N, Niikawa N, et al. Monozygotic twins with discordant sexual phenotypes due to different ratios of mosaicism of 47,X,idic(Y),idic(Y)/46,X, idic(Y)/45,X. Endocr J. 2002;49(4):497–501. Seifer DB, Meyers-Seifer CH, Lavy G, Genel M, DeCherney AH, Yang-Feng TL. Laparoscopic adnexectomy in a prepubertal turner mosaic female with isodicentric Y. Hum Reprod. 1991;6(4):566–7. Mizuno K, Kojima Y, Kurokawa S, Mizuno H, Kohri K, Hayashi Y. Laparoscopic diagnosis and treatment of a phenotypic girl with mosaic 45,XO/46,X,idic(Y) mixed gonadal dysgenesis. J Pediatr Surg. 2009;44(1):e1–3. Kawabata G, Sato M, Okamoto Y, Mizuno Y, Akematsu T, Okada H. Laparoscopic removal of gonads in a Turner’s syndrome mosaic female patient with isodicentric Y chromosome. Int J Urol. 2000;7(11):425–6. Marrocco G, Poscente M, Majore S, De Bernardo C, Rinaldi R, Del Porto G, et al. Clinical management and molecular cytogenetic characterization in a 45,X/46,X,idic(Yp) patient with severe hypospadia. J Pediatr Surg. 2003;38(8):1258–62.