Objective: Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. There have been extensive studies focusing on the identification of the Down Syndrome Critical Region (DSCR). Our case aims in providing evidence that duplication of 21q21.1-q21.2 is not included in the DSCR and that it has no clinical consequences on the phenotype.

Methods: Due to missing the appropriate gestational age for serological screening, Non-Invasive Prenatal Testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. Then further ultrasound-guided amniocentesis followed by cytogenetic analysis and chromosomal microarray analysis (CMA) was conducted to confirm the maternally inherited duplication detected by NIPT.  

Results: The result of NIPT revealed a 5.8Mb maternally inherited duplication of 21q21.1-q21.2. To test whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted and the result of CMA with amniotic fluid showed a 6.7Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009) for the fetus. This partial duplication of 21q21.1-q21.2 for the fetus was maternally inherited. The pregnant woman and her family decided to continue the pregnancy after genetic counseling.

Discussion: There are 20 genes in the segment of 21q21.1-q21.2, including 4 OMIM genes (BTG3(605674), CHODL(607247), TMPRSS15 (606635), NCAM2(602040)). Analysis in mouse revealed that BTG3 expression was high in the ventricular zone of the developing central nervous system. CHODL is a type I transmembrane protein homologous to C-type lectins, mainly expressed in vascular muscle of testis, smooth muscle of prostate stroma, heart muscle, skeletal muscle, crypts of small intestine, and red pulp of spleen. TMPRSS15 gene encodes an enzyme that converts the pancreatic proenzyme trypsinogen to trypsin, which activates other proenzymes including chymotrypsinogen and procarboxypeptidases. Mutations in this gene cause enterokinase deficiency, a malabsorption disorder characterized by diarrhea and failure to thrive. NCAM2 is a human neural cell adhesion molecule gene, and it is recognized as a candidate for involvement in some DS phenotypes. However, the role of NCAM2 in the pathophysiology of DS is unknown. In summary, no gene was found to be definitely related to certain DS phenotypes based on the analysis of the above four OMIM genes.

The DSCR region that can lead to clinical phenotypes mainly include21q22.3, 21q22.13, 21q11.2-q21.3 and so on. Phenotypes caused by these regions include hypotonia, brachycephaly, sandal gaps, joint hyperlaxity, developmental delay, speech delay and congenital heart defects etc. Actually, this case had a duplication of 21q21.1-q21.2 without involving DSCR region of 21q22.13-q22.3 and presented no DS phenotype as well as any other clinical phenotypes. At present, most of the studies focus on the identification of the pathogenic regions or genes of trisomy or partial trisomy 21. There have been nearly no studies targeting the non-pathogenic regions of duplication or partial duplication of chromosome 21. Indeed, studies about non-pathogenic region of chromosome 21 are as important as identification of its pathogenic regions for prenatal diagnosis.

In conclusion, this report can provide evidence to perform cutting-edge analysis of trisomy or partial trisomy 21 with normal phenotype.