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Robertsonian Translocations: An Overview of 872 Robertsonian Translocations Identified in a Diagnostic Laboratory in China

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Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population.
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RESEARCH ARTICLE
Robertsonian Translocations: An Overview of
872 Robertsonian Translocations Identified
in a Diagnostic Laboratory in China
Wei-Wei Zhao
1
, Menghua Wu
1
, Fan Chen
1
, Shuai Jiang
1
, Hui Su
1
, Jianfen Liang
1
,
Chunhua Deng
1
, Chaohui Hu
1
, Shihui Yu
1,2
*
1 KingMed Genome Diagnostic Laboratory, Guangzhou, China, 2 Department of Laboratory Medicine,
University of Washington School of Medicine and Seattle Childrens Hospital, Seattle, Washington, United
States of America
These authors contributed equally to this work.
* shihui.yu@seattlechildrens.org
Abstract
Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births,
making this type of rearrangement the most common structural chromosomal abnormalities
seen in the general population. In this study, we reports 872 cases of ROBs from 205,001
specimens karyotyped postnatally in a single accredited laboratory in China, including 583
balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-
three percent of the balanced ROBs observed were adults with infertility, miscarriage, or off-
spring(s) with known chromosomal abnormalities. Significant excess of females were found
to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight
percent of the unbalanced ROBs observed were children with variable referral reasons. Al-
most all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,
XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple
novel ROB karyotypes were reported in this report. This study represents the largest collec-
tions of ROBs in Chinese population.
Introduction
Robertsonian translocations (ROBs) are chromosomal rearrangements that result from the fu-
sion of the entire long arms of two acrocentric chromosomes. The karyotype of a balanced
ROB shows only 45 chromosomes in which the translocation chromosome contains the two
complete long arms of the two acrocentric chromosomes involved while the short arms of the
two translocated chromosomes are lost. ROBs have an estimated incidence rate of 1/1000
births, making this type of rearrangements the most common structural chromosomal abnor-
malities seen in the general population [13]. Although all human acrocentric chromosomes
(chromosomes 13, 14, 15, 21, and 22) are capable of participating in ROB formation, producing
5 types of homologous ROBs and 10 types of heterologous ROBs, the distribution of different
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 1/14
OPEN ACCESS
Citation: Zhao W-W, Wu M, Chen F, Jiang S, Su H,
Liang J, et al. (2015) Robertsonian Translocations:
An Overview of 872 Robertsonian Translocations
Identified in a Diagnostic Laboratory in China. PLoS
ONE 10(5): e0122647. doi:10.1371/journal.
pone.0122647
Academic Editor: Yan W. Asmann, Mayo Clinic,
UNITED STATES
Received: November 11, 2014
Accepted: February 11, 2015
Published: May 1, 2015
Copyright: © 2015 Zhao et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: KingMed Genome Diagnostic Laboratory
provided support in the form of salaries for authors
WWZ, MHW, FC, SJ, JFL, CHD, CHH, but did not
have any additional role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript. The specific roles of
these authors are articulated in the author
contributions section.
ROBs in the general population is nonrandom, with der(13q14q) and der(14q21q) constituting
*85% of all ROBs and all other types of ROBs constituting the remaining *15% of these
translocations. The majority of heterologous ROBs are inherited from a carrier parent and the
minority of them form de novo mainly in th e stage of meiosis I of oogenesis whereas almost all
homologous ROBs form de novo mitotically [4,5]. It was proposed that the high prevalence of
ROBs is because of the similarities of the DNA sequences shared by the short arms of acrocen-
tric chromosomes which confer susceptibility to chromosome rearrangement [3]. The predom-
inance of the der(13q14q) and der(14q21q) may be specifically due to homologous but
inverted segments in these pairs of chromosomes that facilitate crossover and recombination,
while the variable breakpoints in the uncommon translocations occur randomly [6,7]. Most
carriers of a balanced ROB, both heterologous and homologous, do not display an obvious phe-
notype and remain undetected until they attempt to reproduce. However, a heterologous ROB
carrier can produce offsprings with either a normal karyotype or a balanced ROB through al-
ternate segregation of meiosis or produce unbalanced gametes through adjacent segregation of
meiosis leading to increased risk of infertility, spontaneous miscarriage, offsprings with unbal-
anced translocations, and uniparental disomy (UPD) or UPD-related imprinting disorders if
chromosomes 14 and 15 are involved. In contrast, a homologous ROB carrier can only produce
unbalanced gametes (either disomic or nullisomic), when fertilized with a normal gamete, lead-
ing to the formation of conceptuses with either trisomy or monosomy. Occasionally a homolo-
gous ROB carrier could have a phenotypically normal child by postzygotic trisomy rescue
mechanism in which the free chromosome from the normal gamete is lost at a very early mito-
sis. Of the 5 acrocentric chromosomes, unbalanced der(21;21) is the most common chromo-
somal category after standard trisomy 21 resulting in Down syndrome (DS), conceptuses with
an unbalanced der(13) are occasionally viable whereas none of the other unbalanced possibili-
ties (trisomies 14, 15, and 22, and any of the monosomies) are viable.
There are about 16 million newborns in China in 2011, of which 5.6% are affected by differ-
ent types of birth defects (Report on birth defects in China, 2012. http://www.gov.cn/gzdt/att/
att/site1/20120912/1c6f6506c7f811 bacf9301.pdf). Chromosomal abnormalities including triso-
mies are considered to be one of the most important causes of the birth defects. Different from
the birth defects surveillance systems in developed countries where almost all babies with sus-
pected DS and other chromosomal abnormalitiesrelated disorders will be karyotyped to con-
firm the diagnosis [4,810], only a small number of these types of patients have been
karyotyped in China due to limited access to chromosomal analyses. Given the fact that ap-
proximately 5% of individuals with DS in Caucasians are due to a translocation involving chro-
mosome 21, and about 95% of them are ROBs [2], it is invaluable in many ways to know the
prevalence of both balanced and unbalanced ROBs in Chinese populations. We noticed that a
couple of studies reported some data involving ROBs in small sample sizes of Chinese popula-
tions [11,12]. In the current study, we shared our large collection of both balanced and unbal-
anced ROBs identified postnatally in a single accredited laboratory in China.
Materials and Methods
From Jan., 2011 to June, 2014, we successfully performed karyotype analyses for 205,001
human postnatal specimens in our CAP and ISO 15189 accredited central laboratory in
Guangzhou, Guangdong province, China, including 98,686 (48.14%) males, 105,995 (51.70%)
females, and 320 (0.015%) individuals with ambiguous or unknown gender. The male/female
ratio in this cohort for known individuals is 0.93 (98,686 / 105,995). Referral reasons for testing
varied greatly. The majority of children referred for testing involved one or more of the follow-
ing clinical findings: developmental delay (DD), autism, dysmorphic features (DF), seizures, or
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 2/14
Competing Interests: The authors declare that
WWZ, MHW, FC, SJ, HS, JFL, CHD, and CHH are
employees of KingMed Genome Diagnostic
Laboratory, a commercial clinical testing company in
China. SY is an academic consultant of KingMed
Genome Diagnostic Laboratory. There are no
patents, products in development or marketed
products to declare. This does not alter the authors'
adherence to all the PLOS ONE policies on sharing
data and materials.
Table 1. Total Cases of balanced Robertsonian translocations (ROBs) detected in this study.
Subtypes der(13;13) der(13;14) der(13;15) der(13;21) der(13;22) der(14;14) der(14;15) der(14;21)
TMFT M F TMFTMFTMFTMFTMFT MF
Number 5 2 3 344 164 180 24 9 15 16 7 9 14 4 10 4 1 3 23 5 18 86 35 51
Percentages
(%)
0.86 0.34 0.51 59.01 28.13 30.87 4.12 1.54 2.57 2.74 1.20 1.54 2.40 0.69 1.72 0.69 0.17 0.51 3.95 0.86 3.09 14.75 6.00 8.75
M/F Ratio 0.67 0.91 0.60 0.78 0.40 0.33 0.28 0.69
Adjusted M/F
Ratio*
0.72 0.98 0.65 0.84 0.43 0.36 0.30 0.74
Table 1B. Balanced Robertsonian translocations (ROBs) detected in adults.
Subtypes der(13;13) der(13;14) der(13;15) der(13;21) der(13;22) der(14;14) der(14;15) der(14;21)
TMFT M F TMFTMFTMFTMFTMFT MF
Number 523323151172239141358124841322517803347
Percentages
(%)
0.92 0.37 0.55 59.38 27.76 31.62 4.23 1.65 2.57 2.39 0.92 1.47 2.21 0.74 1.47 0.74 0.18 0.55 4.04 0.92 3.13 14.71 6.07 8.64
M/F Ratio 0.72 0.94 0.69 0.67 0.54 0.36 0.32 0.75
Adjusted M/F
Ratio*
0.77 1.02 0.74 0.72 0.58 0.39 0.34 0.81
Chi Square
Test
NT P>0.5 P>0.1 P>0.1 P>0.1 NT P<0.02 P>0.1
Table 1C. Balanced Robertsonian translocations (ROBs) detected in children.
Subtypes der(13;13) der(13;14) der(13;15) der(13;21) der(13;22) der(14;14) der(14;15) der(14;21)
TMFT M F TMFTMFTMFTMFTMFT MF
Number 00021138 1013212020001016 24
Percentages
(%)
0.00 0.00 0.00 53.85 33.33 20.51 2.56 0.00 2.56 7.69 5.13 2.56 5.13 0.00 5.13 0.00 0.00 0.00 2.56 0.00 2.56 15.38 5.13 10.26
M/F Ratio 0.00 1.63 0.00 2.00 0.00 0.00 0.00 0.50
Adjusted M/F
Ratio*
0.00 1.75 0.00 2.15 0.00 0.00 0.00 0.54
Chi Square
Test
NT P>0.1 NT NT NT NT NT NT
Subtypes der(14;22) der(15;15) der(15;21) der(15;22) der(21;21) der(21;22) der(22;22) All types of ROBs
TMFTMFTMFTMFTMFTMFTMFT M F
Number 14 685231661091860614212321583246337
Percentages
(%)
2.40 1.03 1.37 0.86 0.34 0.51 2.74 1.03 1.72 1.54 0.17 1.37 1.03 0.00 1.03 2.40 0.34 2.06 0.51 0.34 0.17 100 42.20 57.80
M/F Ratio 0.75 0.67 0.60 0.13 0.00 0.17 2.00 0.73
Adjusted M/F
Ratio*
0.81 0.72 0.65 0.13 0.00 0.18 2.15 0.78
Table 1B. Balanced Robertsonian translocations (ROBs) detected in adults.
Subtypes der(14;22) der(15;15) der(15;21) der(15;22) der(21;21) der(21;22) der(22;22) All types of ROBs
TMFTMFTMFTMFTMFTMFTMFT M F
(Continued)
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 3/14
Table 1. (Continued)
Subtypes der(14;22) der(15;15) der(15;21) der(15;22) der(21;21) der(21;22) der(22;22) All types of ROBs
TMFTMFTMFTMFTMFTMFTMFT M F
Number 14 68202146891860614212321544227317
Percentages
(%)
2.57 1.10 1.47 0.37 0.00 0.37 2.57 1.10 1.47 1.65 0.18 1.47 1.10 0.00 1.10 2.57 0.37 2.21 0.55 0.37 0.18 100.00 41.73 58.27
M/F Ratio 0.81 0.00 0.81 0.13 0.00 0.18 2.00 0.72
Adjusted M/F
Ratio*
0.87 0.00 0.87 0.14 0.00 0.19 2.15 0.77
Chi Square
Test
P>0.5 NT P>0.5 P<0.001 NT P<0.01 NT P<0.01
Table 1C. Balanced Robertsonian translocations (ROBs) detected in children.
Subtypes der(14;22) der(15;15) der(15;21) der(15;22) der(21;21) der(21;22) der(22;22) All types of ROBs
TMFTMFTMFTMFTMFTMFTMFT M F
Number 0 0032120200000000000039 1920
Percentages
(%)
0.00 0.00 0.00 7.69 5.13 2.56 5.13 0.00 5.13 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 100.00 48.72 51.28
M/F Ratio 0.00 2.00 0.00 0.00 0.00 0.00 0.00 0.95
Adjusted M/F
Ratio*
0.00 2.15 0.00 0.00 0.00 0.00 0.00 1.02
Chi Square
Test
NT NT NT NT NT NT NT P>0.5
doi:10.1371/journal.pone.0122647.t001
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 4/14
multiple congenital anomalies (MCA). The majority of adults referred for testing mainly be-
cause of infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. These
specimens came from all over the mainland of China except several provinces in Western
China. The proportions of specimens from individ uals with Chinese ethnic minorities are not
clearly documented. Given the facts that more than 94% of Chinese in mainland Chin a are
Table 3. Total cases of mosaic/complex Robertsonian translocations (ROBs) detected in this study.
Case Sex Age Karyotype der(13;14) der(13;21) der(14;21) der(21;21) der(21;22) der(22;22)
1 F 0 46,XX,der(14;21)(q10;q10),+18 x
2 F 0 46,XX,der(13;14)(q10;q10),+21 x
3 F 0 46,XX,der(13;14)(q10;q10),+21 x
4 M 0 mos 46,XY,der(21;21)(q10;q10)[40]/45,XY,der
(13;21)(q10;q10)[20]
xx
5 M 0 46,XY,der(13;14)(q10;q10),+21 x
4 M 0 46,XY,der(13;14)(q10;q10),+21 x
7 M 0 46,XY,der(13;14)(q10;q10),+21 x
8 M 0 46,XY,der(13;14)(q10;q10),+21 x
9 M 1 46,XY,der(13;14)(q10;q10),+21 x
10 M 4 46,XY,der(14;21)(q10;q10),t(6;12)(q21;q13),+21 x
11 F 0 44,X,der(13;14)(q10;q10) x
12 F 0 44,XX,der(14;21)(q10;q10),der(14)t(14;22)(q32;
q11.2),-22
x
13 M 0 45,XY,der(21)del(21)(q22)t(21;22)(q10;q10),-22 x
14 F 24 45,XX,der(21;22)(q10;q10),t(3;14)(q27;q13) x
15 F 26 45,X,der(21;22)(q10;q10),del(X)(q21) x
16 M 26 46,XXY,der(13;14)(q10;q10) x
17 F 27 mos 46,XXX,der(13;14)(q10;q10)[32]/44,X,der
(13;14)(q10;q10)[28]
x
18 M 27 46,XXY,der(13;14)(q10;q10) x
19 F 0 mos 45,XX,der(21;21)(q10;q10)[56]/46,XX,der
(21;21)(q10;q10)[4]
x
20 M 0 mos 46,XY,der(21;21)(q10;q10)[14]/46,XY[46] x
21 M 34 mos 45,XY,der(21;22)(q10;q10)[56]/46,XY,der
(21;22)(q10;q10),+21[4]
x
22 F 0 mos 46,XX,der(21;21)(q10;q10)[16]/46,XX[44] x
23 F 21 mos 45,XX,der(22;22)(q10;q10)[23]/46,XX[37] x
24 F 22 mos 45,XX,der(14;21)(q10;q10)[9]/46,XX[51] x
25 F 33 mos 45,XX,der(21;21)(q10q10)[41]/46,XX[19] x
doi:10.1371/journal.pone.0122647.t003
Table 2. Unbalanced Robertsonian translocations (ROBs) detected in Children.
Subtypes 46,der(13;14),+13 46,der(13;21),+21 46,der(14;21),+21 46,der(15;21),+21 46,der(21;21) 46,der(21;22),+21 All types of ROBs
Number T M F T M F T M F T M F T M F T M F T M F
1 0 1 17 6 11 108 57 49 6 4 2 123 64 59 6 4 2 259 135 124
Percentage 0.39 0.00 0.39 6.56 2.32 4.25 41.70 22.01 18.92 2.32 1.54 0.77 47.49 24.71 22.78 2.32 1.54 0.77 100.00 52.12 47.88
M/F ratio 0.00 0.55 1.16 2.00 1.08 2.00 1.09
M/F ratio* 0.00 0.59 1.25 2.15 1.17 2.15 1.17
Notes: T: total; M: male; F: female;
*based on the M/F ratio of the 98,686 males and 105,995 females performed by karyotype analysis.
doi:10.1371/journal.pone.0122647.t002
872 Robertsonian Translocations Identified
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Chinese Han and very few of the tested specimens included in this study were from the West-
ern areas of China where the ethnic minorities are highly concentrated, ROBs included in this
study are not categorized according to their ethnics. All adult participants in this study have
provided their written consent by the participants or their caretakers. We obtained written con-
sent for all minors/children enrolled in this study from their parents or guardians. The institu-
tional review board of KingMed Genome Diagnostic Laboratory approved this study protocol.
Standard chromosomal analyses with trypsin-Giemsa banding were performed on routinely
cultured peripheral blood lymphocytes for all ROBs. Twenty metaphases were microscopically
analyzed for non-mosaic cells and sixty metaphases were analyzed for mosaic cells. Nomencla-
tures were assigned for each ROB based on the international system for human cytogenetic no-
menclature (ISCN 2013). The International System for Human Cytogenetics Nomenclature
(ISCN) 2013 guidelines have standard nomenclature to describe a ROB using abbreviated
der or rob in lower ROB. In this article, a shorthand description for ROBs [e.g., der(13;14),
der(21;21)] has been used throughout although the majority of homologous acrocentric rear-
rangements are likely to be isochromosomes.
Results
Of the 205,001 specimens karyotyped in this study, 872 were identified to have ROBs. These
ROBs are categorized into 4 groups: (1) 583 balanced ROBs (Table 1A1C and S1 Fig, S3 Fig,
S4a Fig, S5S7 Figs, S9S11a Figs, S12 Fig and S15 Fig), (2) 264 unbalanced ROBs ( Table 2 and
S2a Fig, S4B Fig, S8a Fig, S11B Fig, S13 Fig), (3) 9 mosaic ROBs in which either an additional
normal or abnormal cell population was found in addition to the cell population carrying a
ROB (Table 3) and (4) 18 complex ROBs in which multiple genomic abnormalities were pres-
ent (Table 3 and S2c Fig, S2d Fig, S8b Fig, S14 Fig). Two ROBs are grouped into both categories
3 and 4 because they are both mosaic and complex.
Nonrandom distributions of different subtypes of balanced ROBs
The 583 cases with balanced ROBs can be further classified into two subgroups based on their
ages: 544 (93%) adults with ages ranging from 19 to 64 years-old (Table 1A) and 39 (7%) chil-
dren with ages ranging from newborn to 11 years-old (Table 1B). Of the 544 adults with bal-
anced ROBs, 524 (96.32%) are heterologous ROBs and 20 (3.68%) are homologous ROBs. The
distribution of different subtypes of ROBs in these adults is nonrandom, with der(13;14) and
der(14;21) constituting 59.4% and 14.7% respectively, and all other 13 subtypes of ROBs con-
stituting the remaining *26% ROBs with variable proportions from 1.65% for der(15;22) to
4.23% for der(13;15). The 20 homologous ROBs identified in this cohort include 5 der(13;13),
4 der(14;14), 2 der(15;15), 6 der(21;21), and 3 der(22;22).
Of the 39 children (20 females and 19 males) with balanced ROBs, 36 (92.3%) of them are
heterologous and only 3 (7.7%) of them are homologous and all of the 3 homologous ROBs are
der(15;15). Similar to what observed in the adults with balanced ROBs, the distributions of dif-
ferent subtypes of ROBs in these children are nonrandom, with der(13q14q) and der(14q21q)
being predominant, constituting 54% and 15% respectively, and all others constituting the re-
maining *30%.
Significantly skewed male/female ratios in individuals with balanced
ROBs
The male/female ratio of the 544 adults with balanced ROBs is 0.72 (227 males/317 females)
(Table 1B), showing a significant difference from the male/female ratio of 0.93 for the total
cases analyzed in this study (98,686 males and 105,995 females) (p<0.01). The adjusted male/
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 6/14
female ratio in these balanced ROB carriers is 0.77(0.72/0.93), showing an excess of females
being a carrier of balanced ROBs. It was noticed that all 6 der(21;21) carriers are females.
Different from 0.77 of the adjusted male/female ratio in the adults, the adjusted male/fe male
ratio (1.02) was not skewed in the 39 children with balanced ROBs (p>0.5) (Table 1C). In-
creased male/female ratio (1.75) in the der(13;14) subcategory is interesting, although statisti-
cally insignificant (p > 0.10).
Nonrandom distributions of different subtypes of unbalanced ROBs
259 of the 264 individuals with unbalanced ROBs are children with ages ranging from newborn
to 12 years-old (Table 2). The remaining 5 individuals are all females referred for chromosome
analysis because of infertility. Of the 264 individuals with unbalanced ROBs, almost all of them
are unbalanced ROBs involving chromosome 21 except a single ROB with [46,XX,der(13;14),
+13] identified in a newborn girl with multiple congenital anomalies (S2a Fig). The distribution
of different subtypes of unbalanced ROBs in these children are nonrandom, 47.5% for der
(21;21), 41.7% for der(14;21), 6.6% for der(13;21), and 2.3% for both der(15;21) and der
(21;22) respectively.
Male/female ratio in individuals with unbalanced ROBs
Of the 259 children with unbalanced ROBs, the male/female ratio is 1.09 (135/124), when ad-
justed, 1.17 (1.09/0.93). Although more males are observed in this group, statistically the male/
female ratio is not significantly increased (p>0.10).
Mosaic ROBs
The 9 mosaic ROBs in Table 3 are composed of 3 balanced (Cases 23, 24, and 25), 4 unbalanced
der(21;21) (Cases 20, 21, and 22), and 2 unbalanced being both mosaic and complex (case 4
identified in a newborn boy with DS and case 17 identified in a 27 years-old female with atypi-
cal features of Turner syndrome). Four of the 9 mosaic ROBs were identified in children (2
males and 2 females) containing unbalanced der(21;21), and the remaining 5 were identified in
adults (1 male and 4 females).
Complex ROBs
There are 18 complex ROBs including 2 mosaic ROBs mentioned above (cases 4 and 17), and
16 cases in non-mosaic status. In total, 13 cases were observed in childre n and 5 cases in adults.
The 13 complex ROBs in children include: (1) one ROB of trisomy 18 with concurrent exis-
tence of non-contributory der(14;21) [46,der(14;21),+18] (case 1), (2) seven ROBs being stan-
dard trisomy 21 with concurrent existence of non-contributory der(13;14) [46,der(13;14),+21]
(cases 2, 3, 59), (3) one ROB trisomy 21 from contributory der(14;21) with concurrent exis-
tence of a reciprocal translocation between chromoso mes 6 and 12 (case 10), (4) one ROB with
loss of a chromosome X with concurrent existence of der(13;14) [44,X,der(13;14)] (case 11),
(5) one ROB with concurrent existence of a balanced der(14;21) and a der(14) from a translo-
cation between chromosomes 14 and 22 (case 12), (6) one ROB of der(21;22) with a distal dele-
tion on the der(21;21)(case 13), and (7) the mosaic ROB containing an unbalanced der(21; 21)
in one cell population and a balanced der(13;21) in the other cell population (case 4).
The 5 complex ROBs in adults include one ROB with concurrent existence of der(21;22)
and a reciprocal translocation between chromosomes 3 and 14 (case 14), one ROB with con-
current existence of der(21;22) and a deletion on one of chromosomes X (case 15), two ROBs
of Klinefelter syndrome with concurrent existence of non-contributory der(13;14) [46,XXY,der
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 7/14
(13;14)] (cases 16 and 18), and the mosaic one containing two abnormal cell populations, one
has three copies of chromosome X and the other has a single copy of chromosome X, and both
populations contain a balanced der(13;21) (case 17).
Discussion
Balanced ROB carriers
It is well known that balanced ROB carriers usually have normal phenotype, but can have prob-
lem of infertility associated with oligospermia in male adults, miscarriage or infertility in fe-
male adults. Although rare, a variety of abnormal phenotypes were described in some balanced
ROB carriers [1316 ]. Warburton et al estimated that approximately 3.7% of de novo, balanced
ROBs resulted in abnormal phenotypes [16]. Proposed explanations for the abnormal pheno-
types in these balanced ROB carriers include (1) mosaicism arising from postmeiotic trisomy
rescue mainly for heterologous ROBs and monosomy rescue mainly for homologous ROBs,
and (2) aberrant genomic imprinting involving chromosomes 14 and 15, and (3) homozygosity
of autosomal recessively inherited mutations [2,17].
To our knowledge, the current study reported the largest collection of balanced ROBs (in
total 583 balanced ROBs including 544 adults and 39 children). The referral indications for the
39 children (36 heterologous ROBs and 3 homologous ROBs) were variable. Since we dont
have either complete clinical data or thorough genetic/genomic testing information, such as
methylation analysis, we are uncertain whether the balanced ROBs in these children were the
underlying causes for their clinical features. We postulate that the majority of the 36 heterolo-
gous ROBs are likely to be incidental findings for following reasons: (1) clinical referral indica-
tions were diverse within each of the subcategories, for example, among the 21 children with
der(13;14) or the 6 children with der(14;21); (2) the risk to be UPD due to ROBs involving
chromosomes 14 or 15 is estimated to be less than 1% [13,17], (3) the risk for isozygosity for
recessive gene is likely to be very low since none of the common recessive genes suitable for
population screening has its locus on an acrocentric chromosome [ 18]. In contrast, we postu-
late that the der(15;15) present in the 3 newborns might be responsible for their clinical fea-
tures given the fact that the majority of homologous ROBs including der(15;15) are UPD due
to the formation of isochromosomes arising postzygotically [3].
The referral reasons for all of the 544 balanced adult ROBs (524 heterologous ROBs and 20
homologous ROBs) are mainly because of infertility, miscarriage, or offspring(s) with known
ROB abnormalities, consistent with previous findings that balanced ROBs were enriched in in-
dividuals with infertile problems [17,1922]. In addition to their infertile problems, we postu-
late that approximately 3 to 4 individuals out of the 524 heterologous ROB carriers might have
imprinting disorders related to UPD(14) or UPD(15) based on the estimation by Berend et al
that 0.8% of heterologous ROB carriers are likely to be UPD [5,13,17]. Different from these het-
erologous ROB carriers, the majority of the 20 homologous ROBs are likely to be UPD due to
isochromosomes arising postmeiotically, and the 6 of the 20 balanced homologous ROBs [4
der(14;14) and 2 der(15;15)] were likely to have additional clinical features related imprinting
disorders except their reproductive difficulties.
Of the 544 adults ROB carriers with reproductive difficulties, 96.32% is heterologous ROBs
and 3.68% is homologous ROBs. These results is significantly different from the data in infertile
Caucasian ROB carriers reported by Therman et al in which 90% of them were heterologous
and 10% of them were homologous (P<0.01) [5]. Nonrandom distribution of balanced ROB
subcategories were observed in all relevant studies [2,5] including ours, for example, der(13;14)
and der(14;21) constitute 59.4% and 14.7% respectively in the 544 adults ROB carriers with re-
productive difficulties observed in this study. We noticed that the percentage of der(13;14) is
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 8/14
significantly decreased and the percentage of der(14;21) is significantly increased in the current
study when compared with the data reported by Therman et al [5] or with the accumulated
data reviewed by Gardner et al in which th e proportions of der(13;14) and der(14;21) were
74% and 8% respectively [2]. Since there is no available data showing the distribution of bal-
anced ROBs in Chinese population, we are not sure whether these differences between Chinese
and Caucasian with infertile difficulties are due to ethnic difference or any other factors. Given
the facts that almost all of the balanced ROB carriers are phenotypically normal and remain
undetected until some of them experience difficulties to reproduce, the distributions of bal-
anced ROBs in this cohort might not have significant difference from their distributions in gen-
eral population although the balanced ROB carriers were highly concentrated in individuals
experiencing reproductive difficulties.
Excessive females were observed in the 544 adults balanced ROBs with the adjusted male/fe-
male ratio of 0.77 (P<0.01) (Table 1B). This phenomenon was observed previously for both
prenatal and postnatal cases and possible reason for the female predominance is primarily ex-
plained by infertili ty difficulties in male carriers [23,24]. The adjusted male/female ratio (1.02)
in the 39 children is not skewed (Table 1C), which is different from the 544 adults where exces-
sive females were observed. The difference could be explained by different referral reasons be-
tween adults and children requested for chromosomal analysis. When the male/female ratios
in different subcategories of the adult ROBs were further stratified, the adjusted male/female
ratio in der(13;14) subcategory is 1.02, showing similar numbers of males and females in this
subgroup while there are more females in other subcategories although the sample sizes are too
small to reach statistical differences (Table 1B). Consistent with the trend observed in adults, it
is interesting to notice that more males are present in the subcategory of children with der
(13;14), indicating that different formation mechanisms might differentiate der(13;14) subcate-
gory from other ROB subcategories as proposed by Bandyopadhyay et al [6,7].
Unbalanced ROBs
Except a single ROB of trisomy 13 observed in a newborn girl with a karyotype of [46,XX,der
(13;14),+13] (S2a Fig), all remaining 263 of the 264 unbalanced ROBs identified in this study
were ROB of trisomy 21 (Table 2), a finding consistent with known conclusions that, only tri-
somies 21 and 13 out of the acrocentric chromosomes are viable in the newborn. The 263 un-
balanced rob(21) accounted for about 4.6% of the 5,772 individuals with DS (our unpublished
data) which is slightly higher than the 4.1% from a nationwide population-based study in Den-
mark and significantly higher than the 3.3% from the U.S. population-based birth defects regis -
tries [25,26]. Although ascertainments might have caused the differences, ethnic factor cannot
be excluded [27]. We further compared our results with the data reported by Mutton et al in
which they reported the largest systematic collections of data from a single source about the cy-
togenetic and epidem iological findings in DS in England and Wales from 1989 to 2009 [9].
They identified a total 779 ROBs with translational trisomy 21 including 338 (43.4%) der
(21;21) and 441 (56.6%) other subtypes of ROBs. There are no significant differences about the
proportions of different subtypes of unbalanced ROBs between our data and theirs.
Of the 263 non-mosaic unbalanced ROB trisomy 21, 5 of them were adult females and all
remaining 258 were children. All the 5 adult females were living in the countryside and were re-
ferred for chromosome analysis because of infertility. We presume that reasons for these 5 fe-
male individuals being referred for chromosome analysis until they were noticed to have
infertile problems are more likely because of economic-social situations rather than atypical
clinical features of trisomy 21.
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 9/14
Excluding the 5 adult females, the adjusted male/female ratio of the 258 children with ROB
trisomy 21 is 1.17, showing slight higher male proportion in this group. Our data is similar to
the 1.14 of ROB trisomy 21 from the New York State Chromosome Registry on over 10,000 DS
reported from 1977 to 1996 [28], and is also similar to the report by Mutton et al in which
51.6% were male among der(21;21) and 55.1% were male among other subtypes of unbalanced
ROBs [9]. The genetic mechanisms leading to excessive male probands of DS are unknown.
Griffin et al. proposed that some of the excess of males among DS individuals is attributable to
a nondisjunctional mechanism in which the extra chromosome 21 preferentially segregates
with the Y chromosome [29]. When comparing the distribution of different subtypes of unbal-
anced ROBs between the current study with the two prestigious reports mentioned above, simi-
lar proportions were noticed indicating that there are no significant differences about the
distribution of different subtypes of unbalanced ROBs between Caucasians and Chinese [9,28].
Mosaic ROBs
Postnatal mosaic ROBs are rare [24,30,31]. Nine mosaic ROBs (6 females and 3 males) were
identified in the current study, consistent with previous reports that excess mosaic females
were obsevered on individuals with autosomal abnormalities [24,28,32]. Proposed explanations
for this phenomenon include specific chromosome loss in females and an increased rate of res-
cue of trisomy to disomy in female conceptions [24,33]. The formation of these mosaic ROBs
occurred mainly postzygotically, somehow different from non-mosaic ROBs which usually oc-
curred during meiosis [2,3,13]. It was also noticed that different subtypes of mosaic ROBs oc-
curred through different multiple-step mechanisms [30,31,34]. Mosaicism with more than one
ROBs are extremely rare [24]. The karyotype of [45,XY,der(13;21)/46,XY,der(21;21)] identified
in this study has not been reported although two relevant ROBs with possibly similar mecha-
nisms were documented with karyotype of [45,XY,rob(13;21) /46,XY,rea(21;21), +21/46,XY]
[35,36]. Possible mechanisms leading to the formatio n of the mosaicism with more than one
ROBs was proposed by Bandyopadhyay et al [30]. In brief, a sperm containing a normal chro-
mosome 13 and 21 fertilized an egg containing normal chromosome 13 and 21, resulting in a
normal conceptus. Due to ‘‘instability of the paternally inherited chromosome 21, two inde-
pendent rearrangement events occurr ed, resulting in two different cell lines, the balanced rob
(13q21q) cell line formed between the maternal chromosome 14 and the paternal chromosome
21 and the trisomy 21 cell line containing an isochromosome 21 formed from the paternally in-
herited chromosome 21.
Complex ROBs
In the current study, we reported 18 cases with multiple chromosomal abnormalities with at least
one of them involving an acrocentric chromosome. To our knowledge, except [46,der(13;14),
+21] (S2b Fig), [44,X,der(13;14)] (S2c Fig) and [46,XXY,der(13;14)] (S2d Fig) have been observed
previously [9,10], the remaining complex ROB karyotypes have not been reported yet (S8b and
S14 Figs). We noticed that trisomy 18 with an additional balanced de novo der(13;14) was previ-
ously described in two cases, which was similar to the [46,der(14;21),+18] observed in our study
[37,38]. It is not surprised to notice that all the individuals with complex ROBs who could survive
to birth were these with ROBs containing reciprocal translocations or ROBs with double aneu-
ploidies involving chromosomes X, Y and 21. It is also interesting to notice that the 13 children
with complex ROBs have more deleterious karyotypes than that in the 5 adults. These quite un-
common observations involving multiple chromosomal abnormalities could be explained as ran-
dom events or more likely caused by mitotic interchromosomal effect that enhances genetic
instability during early development of embryos of Robertsonian translocation carriers [39].
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 10 / 14
Weaknesses of this study
There are several weaknesses present in this study: (1) bias of ascertainments; (2) incomplete
clinical information about these individual carrying ROBs; and (3) incomplete follow-up mo-
lecular testing, especially for these ROBs with homologous ROBs. Although we think these
weaknesses do not affect the result trends observed in this study, the authors cannot rule out
the possibility of other ROBs present in the population that were not identified (due to selec-
tion bias) and that the clinical impact of the novel ROBs cannot be determined (selection bias
and lack of associated clinical data).
Supporting Information
S1 Fig. A der(13;13) and two copies of chromosomes 14, 15, 21 and 22.
(TIF)
S2 Fig. A der(13;14), and (a) a single copy of chromosomes 14, and two copies of chromo-
somes 13, 15, 21 and 22, (b) a single copy of chromosome s 13 and 14, two copies of chro-
mosomes 15 and 22, and three copies of chromosome 21, (c) a single copy of chromosomes
X and 14, and two copies of chromosomes 15, 21 and 22, (d) a single copy of chromosomes
Y, 13 and 14, and two copies of chromosomes X, 15, 21 and 22.
(TIF)
S3 Fig. A der(13;15), a single copy of chromosomes 13 and 14, and two copies of chromo-
somes 14, 21 and 22.
(TIF)
S4 Fig. A der(13;21), and (a) a single copy of chromosomes 13 and 21, and two copies of
chromosomes 14, 15 and 22, (b) a single copy of chromosome 13, and two copies of chro-
mosomes 14, 15, 21 and 22.
(TIF)
S5 Fig. A der(13;22), a single copy of chromosomes 13 and 22, and two copies of chromo-
somes 14, 15 and 21.
(TIF)
S6 Fig. A der(14;14) and two copies of chromosomes 13, 15, 21 and 22.
(TIF)
S7 Fig. A der(14;15), a single copy of chromosomes 14 and 15, and two copies of chromo-
somes 13, 21 and 22.
(TIF)
S8 Fig. A der(14;21), and (a) a single copy of chromosome 14, and two copies of chromo-
somes 13, 15, 21 and 22, (b) a der(14;22), a single copy of chromosomes 21 and 22, and two
copies of chromosomes 13 and 15.
(TIF)
S9 Fig. A der(14;22), a single copy of chromosomes 14 and 22, and two copies of chromo-
somes 13, 15 and 21.
(TIF)
S10 Fig. A der(15;15) and two copies of chromosomes 13, 14, 21 and 22.
(TIF)
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 11 / 14
S11 Fig. A der(15;21), and (a) a single copy of chromosomes 15 and 21, and two copies of
chromosomes 13, 14 and 22, (b) a single copy of chromosomes 15, and two copies of chro-
mosomes 13, 14, 21 and 22.
(TIF)
S12 Fig. A der(15;22), a single copy of chromosomes 15 and 22, and two copies of chromo-
somes 13, 14 and 21.
(TIF)
S13 Fig. A der(21;21), a single copy of chromosome 21, and two copies of chromosomes 13,
14, 15 and 22.
(TIF)
S14 Fig. A der(21;22), apparently balanced translocations between chromosomes 3 and 14
[t(3;14)(q27;q13)], a single copy of chromosomes 3, 14, 21 and 22, and two copies of chro-
mosomes 13 and 15.
(TIF)
S15 Fig. A der(22;22) and two copies of chromosomes 13, 14, 15 and 21.
(TIF)
Author Contributions
Conceived and designed the experiments: SY. Performed the experiments: WWZ MHW FC SJ
HS JFL CHD CHH. Analyzed the data: WWZ MHW FC SJ HS JFL CHD CHH SY. Contributed
reagents/materials/analysis tools: MHW FC SJ HS JFL CHD CHH. Wrote the paper: WWZ SY.
References
1. Hamerton JL, Canning N, Ray M, Smith S. A cytogenetic survey of 14,069 newborn infants. I. Incidence
of chromosome abnormalities. Clin Genet. 1975; 8: 223243. PMID: 1183067
2. Gardner R, Sutherland G, Shaffer L. Chromosome Abnormalities and genetic Counseling. Fourth ed.
New Yok, NY: Oxford. 2012.
3. Kim SR, Shaffer LG. Robertsonian translocations: mechanisms of formation, aneuploidy, and uniparen-
tal disomy and diagnostic considerations. Genet Test. 2002; 6: 163168. PMID: 12490055
4. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from
a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991; 87: 8183. PMID: 2037286
5. Therman E, Susman B, Denniston C. The nonrandom participation of human acrocentric chromosomes
in Robertsonian translocations. Ann Hum Genet. 1989; 53: 4965. PMID: 2658738
6. Bandyopadhyay R, Heller A, Knox-DuBois C, McCaskill C, Berend SA, Page SL, et al. Parental origin
and timing of de novo Robertsonian translocation formation. Am J Hum Genet. 2002; 71: 14561462.
PMID: 12424707
7. Bandyopadhyay R, Berend SA, Page SL, Choo KH, Shaffer LG. Satellite III sequences on 14p and
their relevance to Robertsonian translocation formation. Chromosome Res. 2001; 9: 235242. PMID:
11330398
8. Mai CT, Kucik JE, Isenburg J, Feldkamp ML, Marengo LK, Bugenske EM, et al. Selected birth defects
data from population-based birth defects surveillance programs in the United States, 2006 to 2010: fea-
turing trisomy conditions. Birth Defects Res A Clin Mol Teratol. 2013; 97: 709725. doi: 10.1002/bdra.
23198 PMID: 24265125
9. Mutton D, Alberman E, Hook EB. Cytogenetic and epidemiological findings in Down syndrome, En-
gland and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and the Association of
Clinical Cytogeneticists. J Med Genet. 1996; 33: 387394. PMID: 8733049
10. Morris JK, Alberman E, Mutton D, Jacobs P. Cytogenetic and epidemiological findings in Down syn-
drome: England and Wales 19892009. Am J Med Genet A. 2012; 158A: 11511157. doi: 10.1002/
ajmg.a.35248 PMID: 22438132
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 12 / 14
11. Lau TK, Fung HY, Rogers MS, Cheung KL. Racial variation in incidence of trisomy 21: survey of 57,742
Chinese deliveries. Am J Med Genet. 1998; 75: 386388. PMID: 9482644
12. Bishop J, Huether CA, Torfs C, Lorey F, Deddens J. Epidemiologic study of Down syndrome in a racial-
ly diverse California population, 19891991. Am J Epidemiol. 1997; 145: 134147. PMID: 9006310
13. Berend SA, Bejjani BA, McCaskill C, Shaffer LG. Identification of uniparental disomy in phenotypically
abnormal carriers of isochromosomes or Robertsonian translocations. Am J Med Genet. 2002; 111:
362365. PMID: 12210293
14. Berend SA, Horwitz J, McCaskill C, Shaffer LG. Identification of uniparental disomy following prenatal
detection of Robertsonian translocations and isochromosomes. Am J Hum Genet. 2000; 66: 1787
1793. PMID: 10775524
15. Choi BH, Kim UH, Lee KS, Ko CW. Various endocrine disorders in children with t(13;14)(q10;q10)
Robertsonian translocation. Ann Pediatr Endocrinol Metab. 2013; 18: 111115. doi: 10.6065/apem.
2013.18.3.111 PMID: 24904863
16. Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identi-
fied at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet. 1991;
49: 9951013. PMID: 1928105
17. Shaffer LG. Risk estimates for uniparental disomy following prenatal detection of a nonhomologous
Robertsonian translocation. Prenat Diagn. 2006; 26: 303307. PMID: 16491515
18. Ruggeri A, Dulcetti F, Miozzo M, Grati FR, Grimi B, Bellato S, et al. Prenatal search for UPD 14 and
UPD 15 in 83 cases of familial and de novo heterologous Robertsonian translocations. Prenat Diagn.
2004; 24: 9971000. PMID: 15614836
19. Kochhar PK, Ghosh P. Reproductive outcome of couples with recurrent miscarriage and balanced
chromosomal abnormalities. J Obstet Gynaecol Res. 2013; 39: 113120. doi: 10.1111/j.1447-0756.
2012.01905.x PMID: 22672580
20. Franssen MT, Korevaar JC, van der Veen F, Leschot NJ, Bossuyt PM, Goddijn M. Reproductive out-
come after chromosome analysis in couples with two or more miscarriages: index [corrected]-control
study. BMJ. 2006; 332: 759763. PMID: 16495333
21. Qin J, Zheng CG, Du J, Chen K, Tian XX, Xiang L, et al. Analysis of the chromosomal abnormality in
5774 patients with clinical reproductive abnormality and 32 new karyotypes. Yi Chuan. 2009; 31: 142
146. PMID: 19273421
22. Qian WP, Tan YM, Song D, Tan YQ, Lu GX. Cytogenetic study of 1780 cases of spontaneous abortion.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005; 30: 258260. PMID: 16045008
23. Daniel A, Hook EB, Wulf G. Risks of unbalanced progeny at amniocentesis to carriers of chromosome
rearrangements: data from United States and Canadian laboratories. Am J Med Genet. 1989; 33: 14
53. PMID: 2750783
24. Kovaleva NV. Sex-specific chromosome instability in early human development. Am J Med Genet A.
2005; 136A: 401413. PMID: 16001445
25. Zhu JL, Hasle H, Correa A, Schendel D, Friedman JM, Olsen J, et al. Survival among people with Down
syndrome: a nationwide population-based study in Denmark. Genet Med. 2013; 15: 6469. doi: 10.
1038/gim.2012.93 PMID: 22878506
26. Shin M, Siffel C, Correa A. Survival of children with mosaic Down syndrome. Am J Med Genet A. 2010;
152A: 800801. doi: 10.1002/ajmg.a.33295 PMID: 20186777
27. Carothers AD, Hecht CA, Hook EB. International variation in reported livebirth prevalence rates of
Down syndrome, adjusted for maternal age. J Med Genet. 1999; 36: 386393. PMID: 10353785
28. Hook EB, Cross PK, Mutton DE. Female predominance (low sex ratio) in 47,+21 mosaics. Am J Med
Genet. 1999; 84: 316319. PMID: 10340644
29. Griffin DK, Abruzzo MA, Millie EA, Feingold E, Hassold TJ. Sex ratio in normal and disomic sperm: evi-
dence that the extra chromosome 21 preferentially segregates with the Y chromosome. Am J Hum
Genet. 1996; 59: 11081113. PMID: 8900240
30. Bandyopadhyay R, McCaskill C, Knox-Du Bois C, Zhou Y, Berend SA, Bijlsma E, et al. Mosaicism in a
patient with Down syndrome reveals post-fertilization formation of a Robertsonian translocation and
isochromosome. Am J Med Genet A. 2003; 116A: 159163. PMID: 12494435
31. Iwarsson E, Sahlen S, Nordgren A. Jumping translocation in a phenotypically normal male: A study of
mosaicism in spermatozoa, lymphocytes, and fibroblasts. Am J Med Genet A. 2009; 149A: 17061711.
doi: 10.1002/ajmg.a.32984 PMID: 19610103
32. Huether CA, Martin RL, Stoppelman SM, D'Souza S, Bishop JK, Torfs CP, et al. Sex ratios in fetuses
and liveborn infants with autosomal aneuploidy. Am J Med Genet. 1996; 63: 492500. PMID: 8737659
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 13 / 14
33. Benn P. Trisomy 16 and trisomy 16 Mosaicism: a review. Am J Med Genet. 1998; 79: 121133. PMID:
9741470
34. Berend SA, Canun S, McCaskill C, Page SL, Shaffer LG. Molecular analysis of mosaicism for two differ-
ent de novo acrocentric rearrangements demonstrates diversity in Robertsonian translocation forma-
tion. Am J Med Genet. 1998; 80: 252259. PMID: 9843048
35. Lieber E, Shah P. Two Robertsonian translocations in a boy with mental retardation. J Med Genet.
1982; 19: 229232. PMID: 7108921
36. Clarke MJ, Thomson DA, Griffiths MJ, Bissenden JG, Aukett A, Watt JL. An unusual case of mosaic
Down's syndrome involving two different Robertsonian translocations. J Med Genet. 1989; 26: 198
201. PMID: 2523486
37. Lesniewicz R, Posmyk R, Lesniewicz I, Wolczynski S. Prenatal evaluation of a fetus with trisomy 18
and additional balanced de novo Rob(13;14). Folia Histochem Cytobiol. 2009; 47: S137140. doi: 10.
2478/v10042-009-0053-8 PMID: 20067885
38. Jamal A, Mousavi S, Alavi A. Coincidence of trisomy 18 and robertsonian (13; 14). Iran J Public Health.
2012; 41: 9193. PMID: 23113216
39. Alfarawati S, Fragouli E, Colls P, Wells D. Embryos of robertsonian translocation carriers exhibit a mi-
totic interchromosomal effect that enhances genetic instability during early development. PLoS Genet.
2012; 8: e1003025. doi: 10.1371/journal.pgen.1003025 PMID: 23133396
872 Robertsonian Translocations Identified
PLOS ONE | DOI:10.1371/journal.pone.0122647 May 1, 2015 14 / 14
... The incidence of Robertsonian translocations is estimated to be 1/1000 live births. Although all acrocentric chromosomes are capable of participating in Robertsonian translocations, their occurrence in general population is not so random, with der(13q14q) occurring most commonly, having a frequency of 85% and the rest of the Robertsonian translocations accounting for only 15% [12]. Our data also showed similar results with higher frequency of der(13q14q), and one patient with der(13q15q), with a total prevalence of 7.7% (n=5). ...
... Carriers do not show any abnormal phenotypes and remain undetected until they attempt to reproduce. The male carriers experience infertility associated with oligospermia, whereas females experience miscarriage or infertility [12]. ...
... Three male individuals in the current study had Robertsonian translocations, which resulted from the fusion of the long arms of chromosomes 13, 14, or 15. Although all human acrocentric chromosomes, i.e., chromosomes 13, 14, 15, 21, and 22, can participate in Robertsonian translocations chromosomes 13 and 14 are frequently involved constituting almost 85% of all Robertsonian translocations [23,24]. However, in our study, chromosome 15 was not involved, though it is a common occurrence. ...
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Objectives Many women lose their fetuses through miscarriage due to a variety of causes. The incidence of three or more consecutive pregnancy losses is often classified as repeated spontaneous abortion (RSA) and is considered the most frustrating and complex area in reproductive medicine. Parental chromosomal abnormalities, underlying medical condition, heritable or acquired thrombophilias, immunologic abnormalities, infections, and environmental factors are reported to be possible etiologies responsible for RSA. Gametes with unbalanced chromosomes, which are formed when abnormalities exist in parent chromosomes, are one such cause and are responsible for about 50-60% of first-trimester pregnancy loss. This paper aims to identify whether there is an association between chromosomal anomalies in parents and RSA. Method A case-control study was performed on a total sample size of 600 individuals, including 150 couples with a history of RSA and 150 fertile couples as control. The participants were cytogenetically analyzed using G-banding. Associations between variables were tested using Chi-square and Fisher's exact test (a p-value<0.05 was considered significant). Informed consent from participants and institutional ethical clearance was obtained before the research began. Results Chromosomal anomalies were detected in 21 individuals (7%) with a history of RSA. Female preponderance was observed with a female to male ratio of 2.5:1. Structural chromosomal aberrations (SCAs) were detected in 17 patients, with nine (53%) cases showing balanced reciprocal translocation (involving chromosomes 1,3,6,8,12,13,15,16,18,22 and X) and three (17.65%) cases of Robertsonian translocation (exclusively in males). Mosaicism was observed in four (19.05%) cases. A statistically significant positive association (p-value <0.05) was observed between the presence of parental chromosomal anomalies and RSA. Conclusion These results support an association between RSA and parental chromosomal abnormalities. Currently, clinicians treating cases of RSA face challenging clinical conditions. Identifying a cytogenetic cause for RSA may be of great help to clinicians who manage affected couples.
... In a way that supports our study; "Balanced ROB carriers are well known to generally have a normal phenotype, but they can have oligospermia in male adults, abortion in female adults, or infertility associated with translocation," they noted. Although rare, various abnormal phenotypes have been described in some balanced ROB carriers [11]. ...
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Robertsonian translocations (RTs) result from fusion of 2 acrocentric chromosomes (e.g., 13, 14, 15, 21, 22) and consequential losses of segments of the p arms containing 47S rDNA clusters and transcription factor binding sites. Depending on the position of the breakpoints, the size of these losses vary considerably between types of RTs. The prevalence of RTs in the general population is estimated to be around 1 per 800 individuals, making RTs the most common chromosomal rearrangement in healthy individuals. Based on their prevalence, RTs are classified as “common,” rob(13;14) and rob(14;21), or “rare” (the 8 remaining nonhomologous combinations). Carriers of RTs are at an increased risk for offspring with chromosomal imbalances or with uniparental disomy. RTs are generally regarded as phenotypically neutral, although, due to RTs formation, 2 of the 10 ribosomal rDNA gene clusters, several long noncoding RNAs, and in the case of RTs involving chromosome 21, several mRNA encoding genes are lost. Nevertheless, recent evidence indicates that RTs may have a significant phenotypic impact. In particular, rob(13;14) carriers have a significantly elevated risk for breast cancer. While RTs are easily spotted by routine karyotyping, they may go unnoticed if only array-CGH and NextGen sequencing methods are applied. This review first discusses possible molecular mechanisms underlying the particularly high rates of RT formation and their incidence in the general population, and second, likely causes for the elevated cancer risk of some RTs will be examined.
... It was suggested that a high frequency of those two common RobTs may result from a specific mechanism that involves homological recombination between opposite-directed DNA sequences in chromosomes 13 and 21 vs. 14 [18,57,61,82]. Other types of RobTs are known as rare cases [3,82,90]. ...
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Introduction: Robertsonian translocation (RobT) is the central fusion of the long arms of two acrocentric chromosomes, leading to 45 chromosomes in humans. The most common ones are rob(13;14) and rob(14;21) (91%). Other types of RobT are so-called rare cases. In the general population RobTs occur with a frequency of approximately 0.123%, but among men with reproductive failure this value rises 9-fold. Infertility in RobT carriers is associated with the formation of unbalanced spermatozoa resulting from segregation of the chromosomes involved in trivalent during the meiotic prophase. In spermatozoa of many RobT carriers an increased level of chromosomal aneuploidy is observed. Materials and Methods: We examined the hyperhaploidy level of chromosomes 7, 9, 18, 21, 22, X and Y in spermatozoa of 6 RobT unrelated carriers: two carriers with rare rob(13;15), one with rare rob(13;22), and three of the common rob(13;14). Results were compared with the control data from a group of 7 fertile men with a normal karyotype. Fluorescent in situ hybridization (FISH) was applied. Results: We found an increased level of sperm aneuploidy regarding at least one of the analyzed chromosomes in each of the carriers, while in rare RobTs interchromosomal effect (ICE) was observed. Meiotic segregation pattern of a rare rob(13;15) carrier revealed the 76% of normal /balanced spermatozoa. Disucussion: Due to the relatively high population frequency of RobTs, their influence on reproductive failure, hight risk of imbalancement in prenatal diagnosis (7%), and small amount of data for rare RobTs, each newly characterized case is valuable in genetic counseling.
... [1,2] Robertsonian translocations have an approximate incidence rate of 1/1000 births, which makes them one of the most common structural chromosomal rearrangement seen in general population. [3] SCAN QR CODE TO VIEW ONLINE www.ajbls.com DOI: 10.5530/ajbls.2020.9.64 ...
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Thesis
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Article
A review of all prenatal and postnatal diagnoses of trisomy 16 and trisomy 16 mosaicism was carried out in the context of the current understanding of confined placental mosaicism and uniparental disomy (UPD). The prenatal detection of trisomy 16 cells is associated with a high probability of fetal death, preterm delivery, intrauterine growth retardation, and fetal anomalies. Birth defects were typical of those seen in nonmosaic partial duplications of chromosome 16. Surprisingly, anomalies were sometimes limited to a single organ and included some relatively common isolated defects such as a ventricular septal defect, hypospadias, imperforate anus, inguinal hernia, and clubfoot. The risk for abnormality appeared to be higher in those pregnancies in which trisomy 16 cells were identified in amniotic fluid compared to the detection in chorionic villi samples. Contrary to nonmosaic trisomy 16 with an excess of males, mosaic trisomy 16 shows an excess of female karyotypes. Following the prenatal detection of trisomy 16 cells, aneuploid cells are almost never found in fetal or neonatal lymphocytes. Studies on fibroblasts also often fail to confirm the presence of the abnormal cell line even in cases in which multiple anomalies are present. It is likely that trisomy 16 cells are sometimes present in the early developing embryo even though subsequent cytogenetic studies on fetal or neonatal tissues may not detect any aneuploid cells. UPD can be excluded as a mechanism for those anomalies that are common to mosaic trisomy 16 and nonmosaic partial duplications. The term “occult mosaicism” is suggested to describe the situation in which the presence of an abnormal cell line is suspected on the basis of clinical data but unproven by laboratory analysis. Am. J. Med. Genet. 79:121–133, 1998. © 1998 Wiley-Liss, Inc.