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[13].
Among 125 OMIM genes encompassed in 8q24 duplication [Table 1] of
the proband, TRAPPC9 , TSTA3 , KCNK9 and GPAA1have been linked to developmental delay. RECQL4 is suspected to
be linked with cleft palate, while other genes such as KCNQ3 andGRINA 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.MBP is recognized to be an important gene to maintain the
stability of myelin structure and function. GALRL may be related
to the change of growth hormone level. NFATCL is related to
endocardial tissue development. SALL3 and TSHZ1 may be
related to cleft lip and palate phenotype. 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.