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\begin{document}

\title{Genetic Analysis and Prenatal Diagnosis of a Pedigree With Developmental
Retardation due to Paternal 8q/18q Translocation}



\author[1]{Chunyan Jin}%
\author[1]{xuefang li}%
\author[1]{jiao chen}%
\author[1]{Zhiping Gu}%
\author[1]{Tianhui Xu}%
\affil[1]{The Affiliated Taizhou People's Hospital of Nanjing Medical University (Taizhou People’s Hospital)}%


\vspace{-1em}



  
  \date{June 11, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives: To define the pathogenic cause of pedigree and provide
precise genetic counseling for the pregnant woman, we retrospectively
reviewed a pedigree with developmental retardation due to paternal
8q/18q translocation at The Affiliated Taizhou People's Hospital of
Nanjing Medical University. Materials and methods: Karyotype analysis
and CMA detection were carried out%
\end{abstract}%



\sloppy


\textbf{Introduction}

Reciprocal chromosomal translocation (RCT) is one of the most common
human chromosomal abnormalities. Balanced RCT does not contain the
variation in the number of chromosomes, but only the rearrangement of
genetic material{[}1{]}. As we know, balanced RCT carriers will have
greater risk to experience recurrent miscarriages, embryonic death,
infertility or giving birth to defective offspring{[}2{]}.

Copy number variants (CNVs) are also important causes of birth defects,
resulting in various clinical manifestations, including growth and
developmental abnormality, mental retardation, visceral malformation and
special facial features, etc{[}3{]}. At present, various syndromes are
verified to be caused by CNVs, such as 22q11.2 deletion syndrome,
Cri-du-chat syndrome, Williams syndrome and so on{[}4{]}.

Above all, birth defects are important challenges affecting the quality
of the birth population. Genetic counseling as well as prenatal
diagnosis is effective method to decrease the rate of birth
defects{[}5{]}.

In this study, we report the clinical findings detected in a Chinese
pedigree {[}Figure 1{]}. The proband was diagnosed by CMA to carry a
25.6 Mb duplication of 8q24.12-q24.3 and a 16.5 Mb deletion of
18q21.33-q23. Karyotype analysis showed that the karyotype of the
proband is paternally inherited 46,XX,der(18)t(8;18)(q24.1;q21.3). This
is the first of such a kind of karyotype to be reported. At the same
time, the mother of the proband was pregnant for 18 weeks. CMA and
karyotype analysis of amniotic fluid cells indicated that the fetus also
carried the same karyotype as that of the proband. The couple decided to
terminate the pregnancy after genetic counseling. Functional enrichment
analysis of the genes involved was also carried out to find out the key
genes causing the phenotype of the proband.

\textbf{Materials and Methods}

\emph{Subjects}

The proband is an 8-year-old girl with normal parents. She was delivered
full-term of gestation by cesarean section with a birth weight of 3400 g
and a length of 50 cm. There was no specific abnormality identified when
she was delivered. While later, she was found to be unable to crawl at 1
year old. Clinical examination revealed signs of short statue, wide
ocular distance, strabismus, slightly upturned and broad nose, thin
upper lip, slightly hearing loss, protruding joints of the toes and
being nearly unable to speak. The proband was the first child of her
parents with no abnormality recognized during the pregnancy examination.
The result of echocardiography performed at 20 months old was normal. MR
examination of the brain in 2017 showed that the myelin sheath of the
proband was underdeveloped. The mother of the proband had a history of
four miscarriages. She was referred to the genetic counseling clinic
because of abnormal~pregnancy when she was 18-week pregnant with no
abnormality found in the former pregnancy examination.

\textbf{Methods}

\emph{Karyotype Analysis of Peripheral Blood}

0.5mL peripheral blood of proband and her parents were cultured for 72
hrs at 37 with peripheral blood lymphocyte culture medium (Hangzhou
Biozone Science Technology). After that, 80 \selectlanguage{greek}μ\selectlanguage{english}L colchicine (working
concentration 10 \selectlanguage{greek}μ\selectlanguage{english}g/mL) was added and incubated for 65 min at 37.
Hypotonic treatment was performed with 8mL KCl solution (0.075 mol/L)
before 1mL fixed solution (methanol : glacial acetic acid = 3 : 1) was
used for fixation. Total 50 Giemsa--Trypsin--Giemsa (GTG)-banded
metaphase chromosomes were analyzed. For samples with abnormal
chromosomes, a total of 100 metaphases were analyzed.

\emph{Karyotype Analysis of Amniotic Fluid}

10mL amniotic fluid was obtained and cultured at 37 with amniotic fluid
culture medium (Guangzhou Baiyunshan Baidi Biotechnolgy). Before
harvesting, 120 \selectlanguage{greek}μ\selectlanguage{english}L colchicine (working concentration 50 \selectlanguage{greek}μ\selectlanguage{english}g/mL) was added
and incubated for 25 min at 37. After that, 2 mL pancreatin (Gibco) was
added to stop digestion. Unlike peripheral blood, 6 mL of 1\% sodium
citrate solution was used for hypotonic treatment before 1 mL fixed
solution (methanol : glacial acetic acid = 3 : 1) was added for
fixation. Total 50 GTG-banded metaphase chromosomes were analyzed. For
samples with abnormal chromosomes, a total of 100 metaphases were
analyzed.

\emph{Chromosomal Microarray Analysis}

Genomic DNA was extracted from 200 uL peripheral blood or 10 mL amniotic
fluid using QIAamp DNA Blood Mini Kit (QIAGEN). A total of 250 ng DNA
was used to perform CMA using Affymetrix Cytoscan 750K Array
(Affymetrix, SantaClara, USA) followed by manufacturer's instructions.
Raw data was processed by the software of ChAS (Affymetrix, SantaClara,
USA) and then analyzed referring to databases including Decipher, ISCA,
ClinGen, OMIM, PudMed and so on.

\emph{Enrichment Analysis}

GO analysis was performed on the differential genes. The number of
differential genes included in each GO entry was count. Hypergeometric
distribution algorithm was used to calculate the significance of the
enrichment of differential genes in each GO entry. The result of
calculation will return a p-value with rich significance. The lower the
value is, the more significant it is statistically. The enrichment
significance of each term in BP, CC and MF was calculated by Fisher's
exact test. The KEGG data is used to carry out the pathway analysis of
differential genes, and the hypergeometric distribution algorithm is
used to calculate the significance of the enrichment of differential
genes in each pathway. The smaller the p-value, the higher the
correlation between the corresponding pathway and this differential
gene.

\textbf{Results}

\emph{Genetic examination results of the family}

Karyotype analysis of the proband showed 46,XX,der(18) karyotype with a
derivative 18 chromosome. CMA identified a 25.6 Mb duplication of
8q24.12-q24.3 (ranging from position 120,721,382 to 146,295,771) and a
16.5 Mb deletion of 18q21.33-q23 (ranging from position 61,544,455 to
78,013,728) for the proband {[}Figure 2 (A, B){]} and normal CMA results
for her parents {[}Figure 2 (E, F){]}. To trace the origin of the
derivative 18 chromosome and abnormal CNVs of the proband, karyotype
analysis of her parents were performed. It was found that the mother
showed 46,XX karyotype {[}Figure 3 (F){]}, whereas the father was
revealed to be a carrier of balanced RCT with 46,XY,t(8;18)(q23;q21.3)
karyotype {[}Figure 3 (C, D){]}. Taking together, the karyotype of the
proband was finally to be recognized as
46,XX,der(18)t(8;18)(q24.1;q21.3)pat with a derivative 18 chromosome
{[}Figure 3 (A, B){]}. Results of CMA and karyotype analysis of amniotic
fluid cells were the same as that of the proband {[}Figure 2 (C, D),
Figure 3 (E){]}. The couple decided to terminate the pregnancy after
genetic counseling.

\emph{Results of gene enrichment analysis}

The GO analysis results of deleted OMIM gene showed that the first three
terms of smallest p-value were serine-type endopeptidase inhibitor
activity (Term ID: GO: 0004867), carboxypeptidase activity (Term ID: GO:
0004180) and translation from RNA polymerase II promoter (Term ID: GO:
0006366) {[}Figure 4 (A){]}. Results of KEGG analysis showed that the
first three paths with the smallest p-value were histidine metabolism
(Term ID: path: hsa00340), beta-Alanine metabolism (Term ID: path:
hsa00410) and arginine and line metabolism (Term ID: path: hsa00330)
{[}Figure 4 (B){]}. GO analysis results of duplicated OMIM genes showed
that the first three terms with the smallest p-value were anchored
component of membrane (Term ID:GO:0031225), C-terminal protein
lipidation (Term ID:GO:0006501) and cell response to potassium ion (Term
ID: GO: 0035865) {[}Figure 4 (C){]}. The entry with statistical
significance in the KEGG analysis results was aldosterone synthesis and
secretione (Term ID:path:hsa04925) {[}Figure 4 (D){]}.

\textbf{Discussion}

Carriers of balanced translocation usually have no phenotypic
abnormality since there is no increase or decrease of genetic material.
However, the tetrahedron will be formed during the association of
homologous chromosome in meiosis, forming 18 gametes with only one
normal and one balanced. While the other 16 are unbalanced, resulting in
the risk of abortion, stillbirth or deformity due to (part) monosomy or
(part) trisomy{[}6{]}. As a result, genetic counseling for balanced RCT
is particularly important. The key points of genetic counseling for
these carriers mainly include: informing them of the probability of
having a normal fetus, selecting the mode of pregnancy reasonably, and
performing prenatal diagnosis during pregnancy{[}7{]}. In this study,
the abnormal CNVs of the proband and the fetus are both caused by their
father who is a carrier of balanced RCT. The previous four abortions of
the mother of the proband should be related to the partial monosomy or
trisomy caused by the paternally balanced RCT. The pregnancy termination
of this time could be avoided if the family had genetic counseling
earlier.

Only a few researches of 8q duplication have been reported, mainly
involving 8q-ter duplication{[}8{]}. Phenotypes of 8q duplication were
various. Digilio's research concluded that duplication of genes located
on 8q could be an important cause of conotruncal cardiac defects{[}9{]}.
Rezek et al. reported that duplication of 8q22.1-8q24.3 was associated
with syndromic bilateral cleft lip/palate{[}10{]}. Macayran et al.
suspected that duplication of 8q22.1-q24.1 was associated with bipolar
disorder and speech delay{[}11{]}. Other reported phenotypes include
dysmorphic facial features, renal malformations, hypoplastic and absent
patella and so on{[}12{]}. The proband in this family presented a 25.6
Mb duplication of 8q24. It is reported that dysmorphic features of 8q24
duplication contains thin upper lip, slightly upslanting palpebral
fissures, slightly upturned and broad nose, hypertelorism, micrognathia
and mild psychomotor developmental delay\textsuperscript{{[}13{]}}.
Among 125 OMIM genes encompassed in 8q24 duplication {[}Table 1{]} of
the proband, \emph{TRAPPC9} , \emph{TSTA3} , \emph{KCNK9} and
\emph{GPAA1}have been linked to developmental delay. \emph{RECQL4} is
suspected to be linked with cleft palate, while other genes such as
\emph{KCNQ3} and\emph{GRINA} have been associated with epilepsy{[}8,
14{]}. Four of these features were present for the proband, including
thin upper lip, strabismus, broad nose and psychomotor developmental
delay. No phenotype of cardiac abnormality or cleft lip and palate was
showed for this proband.

Partial deletion of the 18q is a rare chromosomal abnormality which
occurs in about 1 / 40000 of live births{[}15{]}. The partial deletion
of 18q of the proband reported in this study was caused by the balanced
RCT of her father's chromosome 18 and chromosome 8. The mother of the
proband was 18-week-pregnant when referred to us. She decided to
terminate~the~pregnancy because of the same karyotype of the fetus as
that of the proband. The clinical phenotypes of the patients with 18q
deletion were different due to the location and length of the deletion
fragments. It is difficult to analyze the correlation between genotype
and phenotype since the 18q partial deletion fragments are relatively
large{[}16{]}. Some critical regions have been reported to be associated
with several features, including delayed myelination (18q22.3-q23), GH
deficiency (18q22.3-q23), congenital aural atresia (18q22.3),
microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33,
18q22.3-q23){[}17{]}. Several key genes have been reported as
well.\emph{MBP} is recognized to be an important gene to maintain the
stability of myelin structure and function. \emph{GALRL} may be related
to the change of growth hormone level. \emph{NFATCL} is related to
endocardial tissue development. \emph{SALL3} and \emph{TSHZ1} may be
related to cleft lip and palate phenotype. \emph{TSHZ1} gene has also
been associated with congenital vertical talus{[}18-22{]}.

The deletion of 18q21.33q23 for the proband covers most of the above key
pathogenic areas and important genes, therefore overlaps some of the
above phenotypic characteristics. Main phenotypes of the proband involve
short statue, wide ocular distance, strabismus, slightly upturned and
broad nose, thin upper lip, slightly hearing loss, protruding joints of
the toes and being nearly unable to speak and dysmyelination. Cody et
al. reported that patients had various features even with same
deletions, implying the existence of penetrance with associated
phenotypes{[}16{]}. In deed, ultrasonic examination of the proband's
mother indicated that the fetus had begun to show the phenotype of
lateral ventricle widening during the process of waiting for
amniocentesis results.

Derivative chromosomes of this case due to translocations involving 8q
and 18q has never been reported previously. We compared the phenotypes
of this proband with other 8q duplication or 18q deletion patients
{[}Table 2{]}. It is difficult to determine which CNVs cause the
phenotype of the proband according to the existing information since
some traits of 8q duplication and 18q deletion were both observed. In
addition, this proband was nearly unable to speak. This phenotype has
never been mentioned to be associated with 8q duplication or 18q
deletion before. Above all, this research adds to the literature that
duplication of 8q24.12-q24.3 and deletion of 18q21.33-q23 may result in
variable phenotypes even with the same CNVs and reflects the importance
of prenatal diagnosis and genetic counseling.

Magnetic resonance examination showed that myelin sheath of the proband
was poorly developed. 80\% - 90\% of the brain myelin sheath growth
retardation was related to genetic factors including gene mutation,
chromosome abnormality, protease metabolism abnormality, enzyme
deficiency, etc. The main symptoms include brain growth retardation,
lagging behind peers in sports and language. Dysplasia of brain myelin
sheath will lead to cognitive impairment of patients, especially for
young children. For example, there are obstacles in memory, great
difficulties in learning new things, and inattention{[}23{]}.

The enrichment results of deleted OMIM gene showed that it was related
to the metabolic process of various enzymes and amino acids. The normal
metabolism of amino acids is an important basis for life activities. All
tissues and cells of the body can carry out amino acid metabolism,
including deamination, decarboxylation, ammonia metabolism, oxidative
decomposition capacity and other processes as well as participating in
protein synthesis. Liver, kidney and muscle are important tissues and
organs for amino acid metabolism, playing important roles in the
metabolism of amino acids in the body. Abnormal amino acid metabolism is
closely related to the occurrence of human diseases.

The number of missing and repetitive fragments containing various number
of genes of the proband was large. It is considered that the possible
missing genes have a greater impact on the phenotype of the proband
through enrichment analysis although the missing fragments are smaller
than the duplicates. n conclusion, it needs further research that which
gene or genes play a major role in the pathogenesis.

\textbf{Ethics Approval}

This study was approved by the Affiliated Taizhou People's Hospital of
Nanjing Medical University (Taizhou People's Hospital).

\textbf{Consent to participate}

Written informed consent was obtained from the parents.

\textbf{Consent to publish}

All of the analyzed samples were obtained with signed informed consent.

\textbf{Availability of data and material}

The data that support the findings of this study are available from the
corresponding author.

\textbf{Funding}

No funding.

\textbf{Author Contributions}

TX, and CJ conceived and designed the study. XL, JC, and ZG performed
the experiments. TX and CJ wrote the manuscript. All co-authors have
read the manuscript and agreed with its content. This manuscript was
revised by all authors.

\textbf{Conflict of Interest}

The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a
potential conflict of interest.

\textbf{Acknowledgments}

We thank nurse Pei Yu for drawing peripheral blood of the patient and
her parents. We also thank the patient and her family for taking part in
this research.

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Table 1. OMIM genes identified by CMA of dup 8q24 and del 18q21.33q23\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Microarray nomenclature\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Size (kbp)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Cytoband start\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Cytoband end\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
OMIM genes count\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
OMIM genes\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
arr{[}hg 19{]} 8q24.12q24.3(120,721,382-146,295,771)x3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
25574\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
q24.12\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
q24.3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
125\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{TAF2, DSCC, DEPTOR, COL14A1, MRPL13, MTBP, SNTB1, HAS2, HAS2-AS1,
ZHX2, DERL1, ZHX1, ATAD2, FBXO32, ANXA13, TMEM65, TRMT12, RNF139,
NDUFB9, MTSS1, SQLE, WASHC5, NSMCE2, TRIB1, FAM84B, PCAT1, PCAT2,
PRNCR1, CASC19, CCAT1, CASC21, CASC8, POU5F1B, CASC11, MYC, PVT1,
CCDC26, GSDMC, FAM49B, ASAP1, ADCY8, EFR3A, OC90, HHLA1, KCNQ3, LRRC6,
TG, SLA, PTCSC1, WISP1, NDRG1, ST3GAL1, ZFAT, KHDRBS3, COL22A1, KCNK9,
TRAPPC9, CHRAC1, AGO2, PTK2, DENND3, GPR20, PTP4A3, ADGRB1, ARC, JRK,
PSCA, LY6K, SLURP1, LYNX1, LY6D, GML, CYP11B1, CYP11B2, LY6E, LY6H,
GPIHBP1, GLI4, TOP1MT, RHPN1, MAFA, GSDMD, NAPRT, EEF1D, PYCR3, TSTA3,
FAM83H, SCRIB, PUF60, NRBP2, EPPK1, PLEC, MIR661, PARP10, GRINA, SPATC1,
OPLAH, EXOSC4, GPAA1, CYC1, SHARPIN, MAF1, SCX, BOP1, HSF1, DGAT1,
SCRT1, FBXL6, SLC52A2, CPSF1, SLC39A4, VPS28, TONSL, CYHR1, KIFC2,
FOXH1, PPP1R16A, GPT, RECQL4, ARHGAP39, ZNF34, RPL8, ZNF7, COMMD5,
ZNF16}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
arr{[}hg 19{]} 18q21.33q23(61,544,455-78,013,728)x1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16469\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
q21.33\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
q23\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{SERPINB2, SERPINB10, HMSD, SERPINB8, LINC00305, CDH7, CDH19, DSEL,
TMX3, DOK6, CD226, RTTN, SOCS6, CBLN2, NETO1, FBXO15, TIMM21, CYB5A,
FAM69C, CNDP2, CNDP1, ZNF407, TSHZ1, ZNF516, ZNF236, MBP, GALR1, SALL3 ,
ATP9B, NFATC1, CTDP1, KCNG2 , TXNL4A , ADNP2, PARD6G}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 2. Clinical manifestations of the proband and others patients with
dup (8q22-24) and 18q deletion\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Concolino \emph{et al.} & Wheeler 2010 \emph{et al.} & Cody \emph{et
al.} & This study\tabularnewline
\midrule
\endhead
Chromosomal imbalance & 8q22.2-q24.3 duplication & 8q23.3-q24.21
duplication & 18q deletion & 8q24.12-q24.3 duplication and
18q21.33-q23\tabularnewline
Short stature & + & + & 71\% & +\tabularnewline
Facial features & & & &\tabularnewline
wide ocular distance & - & + & N/A & +\tabularnewline
Strabismus & - & N/A & 38\% & +\tabularnewline
broad nose & N/A & N/A & N/A & +\tabularnewline
Long philtrum & + & - & N/A & +\tabularnewline
Palate abnormality & N/A & N/A & 50\% & -\tabularnewline
Ears abnormality & + & + & 77\% & -\tabularnewline
thin upper lip & + & N/A & N/A & +\tabularnewline
Micrognathia & + & + & N/A & -\tabularnewline
Microcephaly & N/A & N/A & N/A & -\tabularnewline
Neurologic anomalies & & & &\tabularnewline
Delayed myelination & N/A & N/A & 100\% & +\tabularnewline
Hypotonia & - & + & 93\% & +\tabularnewline
mental retardation & + & + & 100\% & +\tabularnewline
Hearing loss & - & + & 75\% & +\tabularnewline
Seizures & - & - & 20\% & -\tabularnewline
Spasticity & N/A & N/A & N/A & -\tabularnewline
limb anomalies & & & &\tabularnewline
cubitus valgus & - & N/A & N/A & -\tabularnewline
Equinovarus & - & + & N/A & -\tabularnewline
distal phalanges hypoplasia & + & - & 64\% & -\tabularnewline
Abnormal toes & + & - & 57\% & +\tabularnewline
Birth defects & & & &\tabularnewline
Congenital cardiac defects & + & - & 54\% & N/A\tabularnewline
Frontal meningocele & + & - & N/A & -\tabularnewline
Bifid uvula & - & + & N/A & -\tabularnewline
\bottomrule
\end{longtable}

+: The feature is present. -: The feature is not present. N/A: not
assessed or not available.

Figure Legends.

Figure 1. Pedigree of the family.

Figure 2. Chromosomal microarray analysis. (A) The result showed a 25.6
Mb duplication of 8q24.12-q24.3 of the proband denoted by a blue bar.
(B) The result showed a 16.5 Mb deletion of 18q21.33-q23 of the proband
denoted by a red bar. (C) The result showed a 25.6 Mb duplication of
8q24.12-q24.3 of the fetus denoted by a blue bar. (D) The result showed
a 16.5 Mb deletion of 18q21.33-q23 of the fetus denoted by a red bar.
(E) The normal CMA result of the proband's mother. (F) The normal CMA
result of the proband's father.

Figure 3. Conventional karyotype analysis. (A) The G-banding result of
the proband showed 46,XX,der(18)t(8;18)(q24.1;q21.3)pat karyotype with
the derivative 18 chromosome denoted by a red arrow. (B) The proband's
partial karyotype of derivative 18 chromosome. (C) The G-banding result
of the proband's father showed 46,XY,t(8;18)(q23;q21.3) karyotype with
the RCT between the long arm of chromosomes 8 and 18 denoted by a red
arrow respectively. (D) Partial karyotype of the proband's father with
t(8;18)(q23;q21.3). (E) The G-banding result of the fetus showed
46,XX,der(18)t(8;18)(q24.1;q21.3)pat karyotype with the derivative 18
chromosome denoted by a red arrow. (F) The G-banding result of the
proband's mother showed 46,XX karyotype.

Figure 4. Enrichment analysis. (A) The GO enrichment results of deleted
OMIM gene. (B) The KEGG enrichment results of deleted OMIM gene. (C) The
GO enrichment results of duplicated OMIM gene. (D) The KEGG enrichment
results of duplicated OMIM gene.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}

\selectlanguage{english}
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