Chromosome Polymorphism and Human Pathology: About 27 Cases of Chromosome 9 Inversion in the Beninese Population

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Open Journal of Genetics, 2021, 11, 23-31
https://www.scirp.org/journal/ojgen
ISSN Online: 2162-4461
ISSN Print: 2162-4453
DOI:
10.4236/ojgen.2021.113003 Aug. 6, 2021 23
Open Journal of Genetics
Chromosome Polymorphism and Human
Pathology: About 27 Cases of Chromosome 9
Inversion in the Beninese Population
Simon Azonbakin1*, Alfred Ouedraogo2, Alexis Ouedraogo2, Daniel Sewadouno1,
Arnaud Agbanlinsou1, Yannick Goussanou1, Marius Adjagba1, Jules Alao3, Anatole Laleye1
1Laboratory of Histology-Reproductive Biology, Cytogenetics and Medical Genetics, Human Biology Unit, Faculty of Health
Sciences, Abomey-Calavi University, Cotonou, Benin
2Laboratory of Histology-Embryology, Cytogenetics and Reproductive Biology, Teaching Hospital of Bogodogo, Ouagadougou,
Burkina Faso
3Department of Pediatric and Medical Genetic, Faculty of Health Sciences, Abomey-Calavi University, Cotonou, Benin
Abstract
The chromosomal polymorphism defined by variations of some chromosom-
al regions of a person (
the constitutive heterochromatin and the short arms of
the acrocentric chromosomes (13 to 15 and 21 - 22))
sometimes highlighted
problems with regard to their safety and their pathogenicity. Polymorphisms
are usually found in the same family and transmitted in the dominant Men-
delian. Chromosome 9 inversion is a frequent phenomenon that some cyto-
geneticists consider as a variant of normal. Despite its classification as a mi-
nor chromosome rearrangement which does not correspond to abnormal
phenotypes, many reports have raised conflicting opinions as well, and
its
complete safety is controversial. 27 cases of inve
rsion of chromosome 9 were
identified in our laboratory. The main indications for karyotype of the case of
inv (9) were congenital cardiopathy (18.5%), sex development disorders of
(18.5%), down syndrome (18.5%), and infertility (14.8%). This study stoo
d
out the observations of many authors who highlighted the involvement of
inv
(9) in the genesis of several pathologies.
Keywords
Inversion, Chromosome 9, Karyotype, Abnormality, Fertility
1. Introduction
Constitutional chromosomal abnormalities are an important cause of miscar-
How to cite this paper:
Azonbakin, S.,
Ouedraogo, A
., Ouedraogo, A.,
Sewadouno,
D
., Agbanlinsou, A., Goussanou, Y., Adjag-
ba, M
., Alao, J. and Laleye, A. (2021) Chro-
mosome
Polymorphism and Human Pa-
thology: About 27 Cases of Chromosome 9
Inversion in
the Beninese Population.
Open
Journal of Genetics
,
11
, 23-31.
https://doi.org/10.4236/ojgen.2021.113003
Received:
February 11, 2021
Accepted:
August 3, 2021
Published:
August 6, 2021
Copyright © 20
21 by author(s) and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access

S. Azonbakin et al.
DOI:
10.4236/ojgen.2021.113003 24
Open Journal of Genetics
riage, infertility, congenital anomalies, and mental retardation in humans. Con-
stitutional chromosomal abnormalities include numeral chromosomal aberrations
that cause aneuploidy and structural chromosomal aberrations such as transloca-
tions, inversions, deletions, and duplications [1]. The frequency of structural
chromosomal abnormalities has been estimated at 0.25% in live-born infants [2]
[3]. Chromosomal polymorphisms of constitutive heterochromatin regions of
chromosomes 1, 9, 16, and the Y chromosome were reported. The pericentric
inversion of chromosome 9 (inv (9)) is one of the most common structural ba-
lanced chromosomal variations and was found in both normal and affected pop-
ulations [4] [5]. The incidence is approximately 1% to 3% in the general popula-
tion [3] [4]. Most cytogeneticists consider it as a normal variant because of the
occurrence of inv (9). Despite its categorization as a minor chromosomal rear-
rangement, which is not related to abnormal phenotype, some reports described
inv (9) in association with subfertility and recurrent abortions, abnormal clinical
conditions, as well as other chromosomal abnormalities [6] [7] [8].
In order to study the frequency and the phenotype associated with inv (9), we
reported 27 cases, in the Laboratory of Histology-Biology of Reproduction, Cy-
togenetics and Medical Genetics of Cotonou, Benin.
2. Methods
It was a retrospective study including cases of inv (9) at the Cytogenetics Labor-
atory of Cotonou from January 1, 2014 to June 30, 2020. The data were collected
in the laboratory’s registers. As they were routine patients, a written approval was
not obtained from the ethical committee of Faculty of Health Science of Cotonou.
The study population includes all the patients admitted to laboratory during
the study period. The karyotype was performed in a G band. The culture tubes
were incubated for 72 hours at 37˚C, CO2 5%. The culture was stopped at the
70th hour by adding 50 μl of colcemide (SigmaR). Hypotonic treatment of the
cells with KCl (0.075 M) followed by fixation in ethanol/glacial acetic acid (3:1
vol; vol). A concentrated suspension of cells was placed on slides and dried, for
25 minutes. The chromosomes were obtained by digestion in a trypsin bath and
stained using 2% Giemsa solution. They were then dried and examined under
the microscope using the programmed image analyzer (Cytovision 7.3.1). The
metaphases were captured using a microscope and interpreted in accordance
with the international system of Human Cytogenetic Nomenclature (ISCN).
3. Results
Over 5-year, 1049 karyotypes were performed. Inv (9) was observed in 27 cases
(2.57 %). The inv (9) was predominant in male subjects with a sex ratio of
1.17.The average age of the patients was 12.65 years with extremes from 03
months to 39 years. The majority (46.15%) of our patients were between 0 and 1
year of age. Table 1 summarizes the clinical and genetypical information about
the cases of inv (9). The main indications for karyotype of the case of inv (9)

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were congenital cardiopathy (18.5%), sex development disorders of (18.5%),
Down Syndrom (18.5%), and Infertility (14.8%). The other indication was facial
dysmorphy (7.4%), Suspicion of Klinefelter syndrome (3.7%), psychomotor de-
lay (3.7%), polymalformative syndrome (3.7%), recurrent abortions (3.7%) and
hypotrophy (7.4%). Table 1 summarized clinical feature of patient with inv chr9
and genotypic finding.
The type of inversion observed was q11-q22.3. We also observed a case with mo-
saicism 46, XX (85%)/46, XX, inv (9), five cases associated with Down’s syndrome
and one case with duplication of chromosome 9 (46, XY, inv (9), dup (q13 P11).
Figures 1-4 show metaphasic finding of some genotypics aspects of inv chr (9).
Table 1. Clinical and genetypical information about the cases of inv chr (9).
Case
Sex
Age (years)
Clinical aspects
Genotypics forms
Case 1
F
0.25 (3 months)
Congenital Cardiopathy
46, XX, inv (9)
Case 2
F
0.33 (4 months)
Developpement sexual disorders (DSD)
46, XX, inv (9)
Case 3
M
0.75 (9 months)
Congenital Cardiopathy
46, XY, inv (9)
Case 4
M
31
Infertility (severe oligospermia)
46, XY, inv (9)
Case 5
M
0.75 (9 months)
Developpement sexual disorders (DSD)
46, XY, inv (9)
Case 6
F
35
Infertility (primary amenorrhea)
46, XX, inv (9)
Case 7
M
0.75 (9 months)
Facial dysmorphia
46, XY, inv (9)
Case 8
F
1
Congenital Cardiopathy
46, XX, inv (9)
Case 9
M
38
Developpement sexual disorders (DSD)
46, XY, inv (9)
Case 10
M
15
Facial dysmorphia
46, XY, inv (9)
Case 11
M
39
Suspicion Klinefelter’s syndrome
46, XY, inv (9)
Case 12 F 0.60 (8 months) Congenital Cardiopathy
46, XX (85%)/46, XX,
inv (9) (15%)
Case 13
F
2
Down syndrome
47, XX, +21, inv (9)
Case 14
F
14
Developpement sexual disorders (DSD)
46, XX, inv (9)
Case 15
M
0.75 (9 months)
Down syndrome
47, XY, + 21, inv (9)
Case 16
M
4
Congenital Cardiopathy
46, XY, inv (9)
Case 17
M
0.58 (7months)
Down syndrome
46, XY, +21, inv (9)
Case 18
M
10
Developpement sexual disorders (DSD)
46, XY, inv (9)
Case 19
M
0.75 (9 months)
hypotrophy
46, XY, inv (9)
Case 20
M
1.83 (22 months)
Psychomotor retardation
46, XY, inv (9)
Case 21
M
1.83 (22months)
Polymalformative syndrome
47, XY, +13, inv (9)
Case 22
M
35
recurrent abortions
46, XY, inv (9)
Case 23
M
0.25 (3 months)
Down syndrome
46, XY, +21, inv (9)
Case 24
F
0.33 (4 months)
Down syndrome
46, XX, +21, inv (9)
Case 25
M
46
Infertility (oligospermia)
46, XY, inv (9)
Case 26
M
33
Infertility (azoospermia hypogonadism)
46, XY, inv (9)
Case 27
M
0.75 (9 months)
Hypotrophy
46, XY, inv (9), dup (q13 P11)

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Open Journal of Genetics
Figure 1. Karyotype showing a case of inv chr9 GTG-banded karyotypes of the lymphocytes from patients with
pericentric inversion of chromosome 9.
Figure 2. Karyotype showing a case of inv chr9 from a femelle. 46, XX, inv (9).

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Figure 3. Karyotype showing a case of inv chr9 from a femelle with trisomy 21. 47, XY, +21, inv (9).
Figure 4. Karyotype showing a case of inv chr9 from a femelle with trisomy 21. 47, XX,+ 21, (inv) 9.

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4. Discussion
The inv (9) is a frequent phenomenon, sometimes considered to be a chromo-
somal polymorphism [7] [9] [10]. Although it does not seem to be correlated
with abnormal phenotypes, many controversial reports have been published in-
dicating that it could lead to abnormal clinical conditions. However, when a
breakpoint is located in a gene, the inversion affects the phenotype and causes
the disease [11].
4.1. Frequency
Inv (9), is one of the most common balanced structural chromosomal aberra-
tions and occurs in approximatively 1% - 1.65% within a normal population. It’s
important to notice that the prevalence of the inv chr9 in the general population
varies with ethnicity [12]. The pericentric inversion of the Heterochromatic re-
gion of chromosome 9 [inv (9)], inv (9) (p11q13), or inv (9) (p12q13), is the
most common pericentric inversion found in the human karyotype [11].
In our study, the prevalence of inv Chr9 was 1.64%. Many other authors have
reported the same observation in their studies with an incidence between 1 and
3% [13]. This incidence may depend on the type of genotipic abnormality asso-
ciated with inv (9). In Japan, Kiyomi Yamada has reported an incidence of 1.65%
of inv (9) among the whole population and 1.52% due to Down syndrome pa-
tient group. Furthermore, male subjects were predominant in our study as well
as reported by some authors [14] [15].
4.2. Mechanism
The human chromosome 9 displays the highest degree of structural variability
[4]. Pericentric inversion involving the secondary constriction region of chro-
mosome 9 is considered to be a normal variant. A recent study described four
unique types of pericentric inversions involving the 9qh region and suggested
that the mechanism leading to appearance of this phenomenon involves break
and reunion at the proposed breakpoints [10] [11]. Study of the heterochroma-
tin organization in the pericentromeric region has revealed homology between
9p11-12 and 9q13-21.1. Such homologous sequences could be involved in the
mechanism that generates the inversion [10] [11]. In our study, the most com-
mon variant is 9p11.1-q13.
4.3. Clinical Feature
Chr 9 pericentric inversions are very rare phenomena. In our series, 27 cases, the
most common clinical sign were: heart disease, abnormalities in sexual devel-
opment and infertility. In Korea, Seon-Yong Jeong
et al.
reported 8 patients with
inv (9) presenting various congenital abnormalities, in particular: polydactyly,
giant Meckel’s diverticulum, poor rotation of the small intestine, cardiomyopa-
thy, pulmonary stenosis [12] [15].
Here, we summarized the literature reviews of some clinical feature on inv (9)

S. Azonbakin et al.
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[16].
Inv (9) and heart disease
We described 5 cases in our series. Few cases of this association were reported.
The gène CFA9 on chromosome 9 is a succeptibility gène involved in the conge-
nital heart defect [12].
Inv (9) and Infertility
Inv (9) is considered to be a predisposing factor for infertility. Five cases were
observed in our study (Oligospermia, azoospermia and primary amenorrhea).
Literature has raised divergent views regarding its correlation with hypofertility,
recurrent abortions, spermatogenesis disorders and/or unbalanced offspring [9]
[17] [18]. Moreover, inv (9), like the other chromosomal polymorphisms, re-
mains an important risk factor of failure in Assistance Reproductive Technology.
Many cases of miscarriages were reported to be associated with inv (9) [6] [7].
However, no statistical analyses were performed in these studies.
Inv (9) and Disorders of Sex Development
Five cases of sex development disturbances were observed in our study. Cases
of micropenis and hypospadias associated with inv (9) have been reported [19]
[20]. The phenotype can be explained by a disruption in the matching of homo-
logous chromosomes during meiosis and or by the existence of genes of interest
at breakpoints. Variants of the SRD5A2 gene are thought to be associated with the
occurrence of abnormal sexual development [21].
Inv 9 and Malignant Hematological Disease
The link between inv (9) and leukemia were frequently reported. Indeed, in a
series of 3809 cases of patients with malignant hematological disease, Sang Guk
Lee has recorded 586 malignant pathologies and 55 chromosome 9 reversals
[22]. This allowed them to conclude that chr9 inv are isolated anomalies that
have no connection with malignant hemopathies. No case of malignant was
found in our study.
Inv (9) and psychiatic disorders
Though some authors in literature have mentioned association of inv (9) and
psychiatric disorders [8]; none case was recorded in our study
Inv chr9 and prenatal pathology
Inv (9) is considered as a polymorphic variation and is one of the most com-
mon forms of autosomal inversion diagnosed prenatally in amniocytes. Yet its
clinical significance remains uncertain. Most publications suggest that this find-
ing is insignificant. However, some articles report on abnormal ultrasonic find-
ings in association, such as hydramnios, anhydramnios, hydroureter, hydro-
nephrosis, encephalocele, and prune belly syndromes [23].
5. Conclusion
This study reinforced the observations of several authors who underline the in-
volvement of chromosome 9 inversion in occurring of various pathologies. Mo-
lecular cytogenetic examinations such as comparative genomic hybridization

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may prove essential to establish the relationship between the genetic abnormali-
ties of this condition and the consequences on the phenotype of the subject.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.
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