Discussion
To evaluate IGHG4 gene in DS patients with low serum IgG4. A molecular diagnosis of the IGHG4 gene revealed a deletion rate of 69.57% (16/23) among DS patients with low IgG4 levels. In contrast, Pan and Hammarström reported heterozygous deletion rates for the IGHG4 gene of 1.5% in the Caucasian population and 4% in the Black population [15]. This discrepancy between the present study and prior work can be attributed to differences in the techniques used by Pan and Hammarström. The authors used a pulsed field gel electrophoresis technique (PFGE), which provides a resolution that can only identify large deletions. In this study, we used a qPCR technique, which identifies smaller deletions.
To further probe the high frequency of this deletion in our study, we studied the number of copies of the IGHG4 gene in a control group of 38 healthy people without DS, finding the deletion rate to be 5.26 %. Together this suggests that the higher rate of deletion in our study resulted from the qPCR technique. Nevertheless, we have only studied the deletions at the level of exon 2. To specify the size of this deletion, it would be interesting to extend qPCR to other exons. Another possible technique for identification would be an array comparative genomic hybridization (array CGH) method, which has very good resolution. According to Pan and Hammarström (2000), deletions are quite rare; thus, defects in the expression of IgG mainly result from poor regulation of the expression of the heavy chain gene of the constant region. However, Olsson et al. identified deletions at the level of the DNA sequence of IgG1, and Zhao et al. showed that there were mutations at the level of the DNA sequence IgG2 [16,17]. Moreover, additional analysis of genetic polymorphisms in individuals with low serum IgG4 levels revealed an association between decreased IgG4 levels and minor structural defect in theIGHG4 gene [18,19]. On the other hand, some data from chromosomal microarray had also defined the potential clinical significance of IGHG4 locus. Heterozygous deletion ofIGHG4 is likely benign according to ClinVar [20].
There is some shortcoming in this study. Though we had provided sufficient evidence to support the conclusion. Therefore, the findings, especially IGHG4 deletion in Down syndrome, need further investigation to confirm this finding. Due to lack of other technique for example CGH array in our laboratory. Therefore, we hope to further improve the above mentioned to provide a basis of molecular investigation in down syndrome particularly, those with low serum IgG4 and have had repeated infection.
In conclusion, the causes of low serum IgG4 in patients with DS are complex and difficult to study, as DS is a polygenic disease. These deficits may be caused by extrinsic factors linked to disturbances present in DS patients, which are most relevant in the presence of heterozygous deletions that favor low levels of IgG. Critically, our data demonstrate high rates of IGHG4 deletion in DS patients with low IgG4. Our findings may inform future recommendations for genetic testing of IGHG4 in DS patients with low levels of IgG4.