Complex Genomic Rearrangements of the Y Chromosome in a Premature Infant

Overview

Journal Mol Cytogenet

Publisher Biomed Central

Specialty Biochemistry

Date 2024 Aug 25

PMID 39183314

Authors

Stephanie A Balow

Alyxis G Coyan

Nicki Smith

Bianca E Russell

Danielle Monteil

Robert J Hopkin

Teresa A Smolarek

Affiliations

Soon will be listed here.

Abstract

Background: Chromoanagenesis is an umbrella term used to describe catastrophic "all at once" cellular events leading to the chaotic reconstruction of chromosomes. It is characterized by numerous rearrangements involving a small number of chromosomes/loci, copy number gains in combination with deletions, reconstruction of chromosomal fragments with improper order/orientation, and preserved heterozygosity in copy number neutral regions. Chromoanagesis is frequently described in association with cancer; however, it has also been described in the germline. The clinical features associated with constitutional chromoanagenesis are typically due to copy number changes and/or disruption of genes or regulatory regions.

Case Presentation: We present an 8-year-old male patient with complex rearrangements of the Y chromosome including a ring Y chromosome, a derivative Y;21 chromosome, and a complex rearranged Y chromosome. These chromosomes were characterized by G-banded chromosome analysis, SNP microarray, interphase FISH, and metaphase FISH. The mechanism(s) by which these rearrangements occurred is unclear; however, it is evocative of chromoanagenesis.

Conclusion: This case is a novel example of suspected germline chromoanagenesis leading to large copy number changes that are well-tolerated, possibly because only the sex chromosomes are affected.

References

Alkhunaizi E, Albrecht J, Aarabi M, Witchel S, Wherrett D, Babul-Hirji R . 45,X/46,XY mosaicism: Clinical manifestations and long term follow-up. Am J Med Genet A. 2023; 194(3):e63451. DOI: 10.1002/ajmg.a.63451. View

Bardsley M, Kowal K, Levy C, Gosek A, Ayari N, Tartaglia N . 47,XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr. 2013; 163(4):1085-94. PMC: 4097881. DOI: 10.1016/j.jpeds.2013.05.037. View

Berglund A, Viuff M, Skakkebaek A, Chang S, Stochholm K, Gravholt C . Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019; 14(1):16. PMC: 6332849. DOI: 10.1186/s13023-018-0976-2. View

Chang H, Clark R, BACHMAN H . The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet. 1990; 46(1):156-67. PMC: 1683543. View

Cools M, Pleskacova J, Stoop H, Hoebeke P, Van Laecke E, Drop S . Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J Clin Endocrinol Metab. 2011; 96(7):E1171-80. DOI: 10.1210/jc.2011-0232. View

Gu H, Jiang J, Li J, Zhang Y, Dong X, Huang Y . A familial Cri-du-Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis. PLoS One. 2013; 8(10):e76985. PMC: 3797133. DOI: 10.1371/journal.pone.0076985. View

Kim J, Park S, Ryu H, Lee D, Lee B, Kim S . Molecular and clinical characteristics of 26 cases with structural Y chromosome aberrations. Cytogenet Genome Res. 2012; 136(4):270-7. DOI: 10.1159/000338413. View

Kloosterman W, Guryev V, van Roosmalen M, Duran K, de Bruijn E, Bakker S . Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet. 2011; 20(10):1916-24. DOI: 10.1093/hmg/ddr073. View

Kurtas N, Arrigoni F, Errichiello E, Zucca C, Maghini C, DAngelo M . Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome). J Med Genet. 2018; 55(4):269-277. PMC: 5869459. DOI: 10.1136/jmedgenet-2017-105125. View

10.

Layman L, Tho S, Clark A, Kulharya A, McDonough P . Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes. Fertil Steril. 2008; 91(3):791-7. PMC: 3888814. DOI: 10.1016/j.fertnstert.2007.12.078. View

11.

Liu P, Erez A, Nagamani S, Dhar S, Kolodziejska K, Dharmadhikari A . Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 2011; 146(6):889-903. PMC: 3242451. DOI: 10.1016/j.cell.2011.07.042. View

12.

Lin Y, Hsu L, Kuo P, Huang W, Chiang H, Yeh S . Partial duplication at AZFc on the Y chromosome is a risk factor for impaired spermatogenesis in Han Chinese in Taiwan. Hum Mutat. 2007; 28(5):486-94. DOI: 10.1002/humu.20473. View

13.

Lindhardt Johansen M, Hagen C, Rajpert-De Meyts E, Kjaergaard S, Petersen B, Skakkebaek N . 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function--a retrospective longitudinal study. J Clin Endocrinol Metab. 2012; 97(8):E1540-9. DOI: 10.1210/jc.2012-1388. View

14.

McGinniss M, Kazazian Jr H, Stetten G, Petersen M, Boman H, Engel E . Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21. Am J Hum Genet. 1992; 50(1):15-28. PMC: 1682523. View

15.

Ross J, Tartaglia N, Merry D, Dalva M, Zinn A . Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. Genes Brain Behav. 2015; 14(2):137-44. PMC: 4756915. DOI: 10.1111/gbb.12200. View

16.

Sinclair A, Berta P, Palmer M, Hawkins J, GRIFFITHS B, Smith M . 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. DOI: 10.1038/346240a0. View

17.

Stetten G, Blakemore K, Wong C, Kazazian Jr H, Antonarakis S . Evidence for involvement of a Robertsonian translocation 13 chromosome in formation of a ring chromosome 13. Mol Biol Med. 1990; 7(6):479-84. View

18.

Telvi L, Lebbar A, Del Pino O, Barbet J, Chaussain J . 45,X/46,XY mosaicism: report of 27 cases. Pediatrics. 1999; 104(2 Pt 1):304-8. DOI: 10.1542/peds.104.2.304. View

19.

Zhou R, Cheng J, Ma D, Tan J, Wang Y, Hu P . Identifying Novel Copy Number Variants in Azoospermia Factor Regions and Evaluating Their Effects on Spermatogenic Impairment. Front Genet. 2019; 10:427. PMC: 6514098. DOI: 10.3389/fgene.2019.00427. View