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.