In this study, we report four prenatal cases of chromosomal with corpus callosum agenesis. The results of CMA revealed two deletions of 4.8M at 1p36.33p36.31 and 3.1M at Xq26.3q27.1 in Fetus 1 and Fetus 2, a inherited deletions of 6.5M at 1q43q44 and duplication of 8.8M at 7q36.1q36.3 in Fetus 3, a paternal 9.52M deletions at 1p36.33p36.22 and 14.3M duplication at 6q25.3q27 in Fetus 4. To our knowledge, Fetus 3 and Fetus 4 results are both due to the unbalanced translocation of parental inheritance resulting in the formation of derived karyotypes 46, XX, der(1) t(1;7) (q43;q36.1) and 46, XY, der(1) t(1;6) (p36.22;q25.3) (Fig. 1;Fig. 2).
Deletion of about 4.8 M in chromosome 1 1p36.33p36.31 region in Fetus 1, which contains 44 OMIM genes such as PRKCZ, SKI, GNB1, and Clinvar, Decipher, OMIM and other databases have been reports cases of disease in this region. The clinical manifestations of patients with missing regions are not completely consistent, and may have clinical manifestations such as brain dysplasia, stunting, hypotonia, epilepsy, congenital heart disease, and hearing disorders[17, 18]. The X chromosome Xq26.3q27.1 region of fetus 2 has a deletion of about 3.1 M, the deletion region contains five OMIM genes: ZIC3, FGF13, F9, MCF2, and ATP11C. The mutation of ZIC3 gene is related to the visceral inversion, the FGF13 gene is in the nerve, which plays a critical role in the phylogenetic process, and the F9 gene mutations are associated with hemophilia. However, the absence of this region is rarely reported, and its clinical significance is not completely clear. The CMA results of Fetus 3 showed there were 8.8M duplication in the 7q36.1q36.3, which contains 51 OMIM genes including SHH, LMBR1, RBM33, etc. The patients with duplication in this area can be pathogenic, including intellectual disability, growth retardation, dysplasia of corpus callosum, special facial features, congenital heart disease and other clinical manifestations. It also have about 6.5M deletions of chromosome 1q43q44 region contains 21 OMIM genes including AKT3, HNRNPU, ZBTB18, etc in Fetus, which is pathogenic, there may be intellectual disability, microcephaly, epilepsy, craniofacial abnormalities and other clinical manifestations. In Fetus 4, who has a 1p36 deletion syndrome that has a 9.52 Mb deletion at the 1p36.33p36.22. Patients with loss of this region may have clinical manifestations such as abnormal brain development, developmental delay, hypotonia, epilepsy, congenital heart disease, and abnormal hearing[17, 18], and there is also about 14.3 Mb duplication in region 6q25.3q27, and patients with duplication in this region may have clinical manifestations such as stunted growth, low intelligence and intellectual disability[22–24].
Numerous studies have described hypoplasia of the corpus callosum patients. Notably, the reported case did not completely reveal genes and chromosomes based corpus callosum abnormalities. Agenesis of the corpus callosum is frequently associated with other hereditary syndrome, at the same time, it is often accompanied by other abnormal phenotypes. It reported that genomic aberration at chromosome 16p13.11 involves in the formation polydactyly, bilateral ventriculomegaly and corpus callosum agenesis. Ratna Tripathy et al.(2018) reported that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, a disease characterized by a striking enlargement of the corpus callosum, cerebellar hypoplasia, and cortical malformations. Suresh Chandran et al described two cases of agenesis of the corpus callosum with interhemispheric cyst. In our study, in addition to the corpus callosum agenesis, the fetal 4 had also venous catheter spectrum abnormalities, cardiac abnormalities with severe tricuspid insufficiency and mild stenosis, compared with dysplasia of white matter.
In this report, after comprehensive genetic counseling, the couples of Fetus 2, Fetus 3 and Fetus 4 ultimately chose to put an end to the pregnancies. Fetus 1 was given by cesarean section due to polyhydramnios in late pregnancy and hypoxia at birth. Postnatal MRI showed patchy long T long T2 signal shadows in bilateral parietal ventricles, and FLAIR sequence lesions with low signal on the left, considering softening lesions or vascular space enlargement; Echocardiography suggested patent ductus arteriosis and patent foramen ovale. The child was born with developmental delay, epilepsy, low muscle tone, poor hearing, poor health, susceptible to colds and fever, and died after several hospitalizations.
Most patients with corpus callosum agenesis have intellectual disability, epilepsy, Asperger's syndrome, learning problems, depression, schizophrenia, delusional disorder, conduct disorder, conversion symptoms and other clinical symptoms from asymptomatic forms to mild or severe neurodevelopment disorders, and also syndronic agenesis of corpus callosum plus patients showed the most severe clinical features while isolated complete agenesis of corpus callosum patients had the mildest symptoms[13, 26]. Although corpus callosum dysplasia is a relatively rare brain malformation, due to its high non-specificity, the corpus callosum dysplasia is the result of multiple factors and genes interacting. And on the other hand, its clinical manifestations are equally unpredictable and very complicated. This makes prenatal genetic counselling more challenging. Therefore, pregnant women should be provided with detailed information on the range of possible phenotypic outcomes of the syndrome during prenatal genetic counseling.
In summary, we reported the prenatal diagnosis of chromosomal microdeletion and microduplication syndrome by CMA testing in four fetuses with agenesis of corpus callosum. CMA should be an active participant in prenatal diagnostic testing after a positive finding of fetal ultrasound anomaly. The results of this study can provide a clinical basis for prenatal diagnostic and genetic counseling of corpus callosum dysplasia.