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We received this case in our hospital showing chromosomal abnormality 45,X/46,X,del(Y)/46,X,idic(Y) Mosaicism with varied clinical feature and biochemical changes. I have written this case report for publication purpose, it should be with high scientific standard. I have just gathered the information and put it one but not modified. i need this to be revised and plagiarism free. this manuscript should be as per fertility and sterility journal style. i will upload one reference case report from the same journal please follow the same. other related journal also i will attach for your reference. reference style also as per the fertility and sterility journal. if you need any further information please ask. Case Report
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
Shin-Yu Lin a,b, Chien-Nan Lee b, Ai-Ying Peng a, Ti-Jia Yuan a,
Dong-Jay Lee c,d,e, Wen-Hsiang Lin c,d, Gwo-Chin Ma c,d,e,f,
Ming Chen a,b,c,d,e,g,h,*
a Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
b Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei,
Taiwan
c Department of Genomic Medicine, Changhua Christian Hospital, Changhua, Taiwan
d Department of Genomic Science and Technology, Changhua Christian Hospital, Changhua, Taiwan
e Laboratory of Genetics, Development, and Systems Biology, Department of Medical Research,
Changhua Christian Hospital, Changhua, Taiwan
f Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science
and Technology, Taichung, Taiwan
g Department of Life Science, Tunghai University, Taichung, Taiwan
h Department of Molecular Biotechnology, College of Biotechnology and Bioresources, Dayeh
University, Changhua, Taiwan
Received 26 February 2018; received in revised form 18 April 2018; accepted 24 April 2018
KEYWORDS
AZF;
CMA;
We present a rare male fetus with karyotype of mosaic 45,X that comprises two types of aberrant Y chromosomes arising de novo (Yq12 deletion and isodicentric Yq11.22). Both types of the
aberrant Y chromosomes lack the AZFc region which are expected to result in oligospermia but
unaffected male external genitalia. Genetic analyses by karyotyping, chromosome microarray
* Corresponding author. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. Fax: þ886 4 7249847.
E-mail addresses: mingchenmd@gmail.com, mchen_cch@yahoo.com (M. Chen).
https://doi.org/10.1016/j.jfma.2018.04.011
0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jfma-online.com
Journal of the Formosan Medical Association (2018) 117, 1027e1031
FISH;
idic(Y);
Karyotyping;
mBAND
(CMA), and multiplex ligation-dependent probe amplification (MLPA) for the fetus revealed
conflicting results. Additional molecular cytogenetics tools including fluorescence in situ hybridization (FISH) and multicolor banding (mBAND) were performed, which help resolving
the discrepancy and delineated the composition of the aberrant Y chromosomes. This report
highlighted the importance of incorporating multiple genetic technologies for accurate characterization of complex chromosomal rearrangements, which aid in the prenatal diagnosis
and genetic counseling.
Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction
Structurally abnormal Y chromosomes are frequently
detected in mosaicism with a 45,X cell line.1 For example,
small marker chromosomes found in Turner syndrome
(45,X) are often evidenced as aberrations of the Y chromosome, such as isodicentric Y (idic(Y)).2 The influence of
aberrant Y chromosomes on gonadal and somatic development is extremely various, reflecting the diversification of Y
chromosome rearrangements found in patients. The causes
of these rearrangements were related to the postmeiotic
and/or postzygotic events, e.g. Y chromosome breakage,
non-disjunction and somatic recombination.2,3 Currently,
only few cases were reported to have different cell lines
with different types of Y-chromosome rearrangements.4e6
We describe a prenatal case with a complicated karyotype (mosaic 45,X with structural abnormal Y chromosomes) which was initially analyzed by different genetic
tools but results were conflicting. Additional molecular
cytogenetic analyses were performed and the compositions
of the abnormal Y chromosomes were delaminated, which
help for the clarification of the diagnostic discrepancy and
genetic counseling.
Case report
A 28 year-old primiparous woman without known medical
history comes to our clinic for regular prenatal visits since
the gestation age (GA) of 8 weeks. At GA Z 12 weeks, the
fetal nuchal translucency was measured as 2.7 mm and the
calculated Down syndrome risk was 1 in 70. At GA Z 17
weeks, she received amniocentesis for genetic analyses.
Cytogenetic investigation of the amniocytes showed a
complicated karyotype of mosaic 45,X, in which two cell
lines with different types of Y chromosome rearrangements
were found, i.e. Yq12 deletion (del(Y)(q12)) and isodicentric Yq11 (idic(Y)(q11)). Four cells with 46,X,þmar
were also noted but these cells were present in single
colony and thus were recognized as level II pseudomosaicism. The Karyotype of the father was normal, thus the
aberrant Y chromosomes of this fetus arose de novo. The
karyotype of the fetus was designated as mos
46,X,del(Y)(q12)dn[79]/45,X[51]/46,X,idic(Y)(q11)dn[2]
(Fig. 1). Genetic analysis using polymerase chain reaction
(PCR) for the Y chromosome deletion in the azoospermia
factor (AZF) region7 showed no PCR product in markers of
sY254 and sY255, indicating the AZFc deletion (Fig. S1).
However, chromosome microarray (CMA) (Affymetrix Cytoscan 750K chip, Thermo Fisher Scientific, California, USA)
performed for the uncultured amniotic fluid showed a
normal male genomic composition without genomic imbalance (i.e. arr(1-22)x2,(X,Y)x1). Prenatal level II sonography
also showed normal male genitalia without fetal structural
anomaly. At GA Z 19 weeks, the woman received the
second time of amniocentesis. Multiplex ligation dependent
probe amplification (MLPA) analysis with SALSA MLPA
probemix P095 aneuploidy assay (MRC-Holland, Amsterdam, the Netherlands) revealed double genetic dosage of
the Y chromosome (i.e. 47,XYY; data not provided since it
was done by another genetic laboratory which refused to
provide the raw data). Fluorescence in situ hybridization
(FISH) and multicolor banding (mBAND) (MetaSystems, Altlussheim, Germany) were subsequently performed for the
subcultured amniotic cells in order to delineate the composite Y chromosomes. Probes for FISH include CEP Y
(DYZ1) (corresponding to the Yq12), CEP Y (DYZ3) (corresponding to the Yp11.1q11.1) and WCP Y (corresponding to
whole Y chromosome painting) (Abbott Molecular, Illinois,
USA). The mBAND was carried out using the Xcyte Y mBAND
probe kit (MetaSystems, Altlussheim, Germany). Of the
20 cells examined, 11 cells had a idic(Y)(q11.22), 4 cells had
two idic(Y)(q11.22), and 5 cells showed no Y material. The
result of the FISH and mBAND analyses was then described
as ish idic(Y)(q11.22)(DYZ3þþ,WCP Yþ,mBAND Yþ,DYZ1-)
[11]/idic(Y)(q11.22)(DYZ3þþ,WCP Yþ,mBAND Yþ,DYZ1-)x2
[4]/ish(mBAND Y-)[5] (Fig. 2AeC). Idiograms of the normal
Y chromosome and the aberrant idic(Y)(q11.22) chromosome were also provided (Fig. 2D and E). Ultrasonography
performed at GA Z 19 weeks showed the external genitalia
of the male fetus is normal (Fig. 3).
Discussion
In this prenatal case, karyotyping, Y chromosome microdeletion screening, CMA, MLPA and FISH/mBAND showed
different results. The seemingly conflicting results among
1028 S.-Y. Lin et al.
karyotyping (a mosaic 45,X male fetus with del(Y)(q12) and
idic(Y)(q11)), Y chromosome microdeletion screening (AZFc
deletion), CMA (arr(1-22)x2,(X,Y)x1) and MLPA (47,XYY) can
be explained by the limitations of each technology. Karyotyping of the Y chromosome is limited by the resolution
so that most of the Y chromosome appears small with
del(Y)(q12) and small number of the Y chromosome had
apparent idic(Y)(q11) appearance. Because the mosaicism
rate of 45,X was not high and only few CMA probes are
available over the long arm of the Y chromosome (also
noted, there is no CMA probe across the heterochromatic
Yq12 region), which rendered the CMA showed a normal
male complement without genomic imbalance. For the
SALSA MLPA probemix P095 Aneuploidy assay, there were
only 5 Y chromosome-specific probes between Yp11.31 and
Yq11.221 (3 probes for the SRY gene at Yp11.31, one probe
at Yq11.21 and one probe at Yq11.221). Therefore, the
MLPA can only detect the cells with idic(Y)(q11.22),
resulting in conclusion of double dosage of the Y chromosome. The FISH and mBAND identified mosaic cells with
45,X, 46,X,idic(Y)(q11.22) and 47,X,idic(Y)(q11.22)x2, but
not the cells with 46,X,del(Y)(q12), which might be related
to the bias of subcultured cells. As a result, each technology has its advantages and disadvantages. None of the
testing results was wrong if we have the panoramic view of
all results in a retrospective way. The final karyotype was
refined as: mos 46,X,del(Y)(q12)dn/45,X.ish(mBAND
Y-)/46,X,idic(Y)(q11.22)dn.ish idic(Y)(q11.22)(DYZ3þþ,
WCP Yþ,mBAND Yþ,DYZ1-)/idic(Y)(q11.22)(DYZ3þþ,WCP
Yþ,mBAND Yþ,DYZ1-)x2.
Mosaic postnatal cases of idic(Y) are associated with
broad phenotypes, including Turner syndrome, ambiguous
genitalia, craniofacial abnormalities, short stature,
incomplete masculinization, male infertility, and less
often, male mental retardation.8 The heterogeneity is
largely attributed to the ratio of cell clones in different
tissues, and the presence or absence of SRY gene.1,9 Cases
diagnosed postnatally due to abnormal phenotypes represented only part of the phenotypic spectrum.6,10 Thus,
when an uncommon sex chromosome abnormality is noted
at prenatal diagnosis, the referenced literature for genetic
counseling should be used carefully. There was a report
describing 12 cases with an idic(Yp) and demonstrated that
the prenatal finding of an idic(Yp), with or without 45,X
mosaicism, is compatible with normal male phenotype in
most cases, particularly in the absence of other anomalies.11 It is difficult for prenatal counseling in such a
complicated karyotype. In this study, because of no structural abnormality noted in the prenatal ultrasound and
some reported cases showed normal clinical outcomes, the
parents decide to keep the pregnancy even though the AZFc
deletion might result in the male spermatogenic failure/
oligospermia.12
Figure 1 Karyotype of the amniocytes (at gestation age of
17 weeks). The karyotype of mos 46,X,del(Y)(q12)dn[79]/45,X
[51]/46,X,idic(Y)(q11)dn[2]. (A) 46,X,del(Y)(q12) (B) 45,X (C)
46,X,idic(Y)(q11).
De novo aberrant Y chromosome in mosaic 45,X 1029
Figure 2 Fluorescence in situ hybridization (FISH) and multicolor banding (mBAND) for the aberrant Y chromosome detected
in amniocytes (at gestation age of 19 weeks). FISH was performed using CEP Y (DYZ1) probe (corresponding to the Yq12, labeling
with indigo fluorophore), CEP Y (DYZ3) probe (corresponding to the Yp11.1q11.1, labeling with red fluorophore), and WCP Y probe
(corresponding to whole Y chromosome painting, labeling with green fluorophore) (Abbott Molecular, Illinois, USA). mBAND was
performed using the Xcyte Y mBAND probe kit (MetaSystems, Altlussheim, Germany). A total of 20 amniocytes were examined for
FISH and mBAND. (A) In 11 cells, single aberrant Y chromosome was found, which was FISH probed with two copies of DYZ3 (yellow
signal Z red DYZ3 probe signal, co-probed with green WCP Y probe signal); (B) in 4 cells, two aberrant Y chromosomes (each
chromosome was FISH probed with two copies of DYZ3) were found; (C) mBAND demonstrated the aberrant Y is isodicentric Yq11.22
(idic(Y)(q11.22)). Idiograms of the (D) normal Y and (E) the aberrant idic(Y)(q11.22).
1030 S.-Y. Lin et al.
Conflicts of interest
The authors have no conflicts of interest relevant to this
article.
Acknowledgement
This study is partly supported by the Research Foundation
of Genetic Study (CCH-7465).
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jfma.2018.04.011.
References
1. Kelly TE, Franko JB, Rogol A, Golden WL. Discordant phenotypes and 45,X/46,X,idic(Y). J Med Genet 1998;35(10):862e4.
2. Reshmi SC, Miller JL, Deplewski D, Close C, Henderson LJ,
Littlejohn E, et al. Evidence of a mechanism for isodicentric
chromosome Y formation in a 45,X/46,X,idic(Y)(p11.31)/
46,X,del(Y)(p11.31) mosaic karyotype. Eur J Med Genet 2011;
54(2):161e4.
3. Fryns JP. Y-chromosome mosaicism with ring Y-chromosome/idic(Y)(p11.2) and “normal” ovarian development. Ann
Genet 2001;44(4):169.
4. Hsu LY. Prenatal diagnosis of 45,X/46,XY mosaicismea review
and update. Prenat Diagn 1989;9(1):31e48.
5. 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):855e69.
6. Tuck-Muller CM, Chen H, Martı ´nez 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):119e29.
7. Krausz C, Hoefsloot L, Simoni M, Tu¨ttelmann F. EAA/EMQN best
practice guidelines for molecular diagnosis of Y-chromosomal
microdeletions: state-of-the-art 2013. Andrology 2014;2(1):
5e19.
8. Alvarez-Nava F, Soto M, Martı ´nez MC, Prieto M, Alvarez 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):443e8.
9. 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):5e8.
10. 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):
108e40.
11. Bruye`re H, Speevak MD, Winsor EJ, de Fre´minville B,
Farrell SA, McGowan-Jordan J, et al. Isodicentric Yp: prenatal diagnosis and outcome in 12 cases. Prenat Diagn 2006;
26(4):324e9.
12. Simoni M, Bakker E, Krausz C. EAA/EMQN best practice guidelines for molecular diagnosis of y-chromosomal microdeletions.
State of the art 2004. Int J Androl 2004;27(4):240e9.
Figure 3 Normal male external genitalia of the fetus (at
gestation age of 19 weeks), (A) 2D ultrasound (B) 3D
ultrasound.
De novo aberrant Y chromosome in mosaic 45,X 1031
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