Down’s Syndrome Genes and Its Inheritance
Down syndrome is a genetic disorder caused by the presence of an additional copy of the chromosome 21 in the cells. The parents of individuals are usually genetically normal and the extra chromosome occurs randomly. Researchers have put effort in understanding the disorder and the conditions leading to its manifestation to well manage and possibly treat the disorder.
Asim A., Kumar A., Muthuswamy S., Jain S., & Agarwal S., (2015) Down syndrome: an insight of the disease. Journal of Biomedical Sciences 22:41
Asim, Kumar, Muthuswamy, Jain, and Agarwal discuss the overview of Down syndrome, its phenotypic diagnosis, and management of the disorder. They also discuss its association with other diseases that manifest alongside DS and various prenatal diagnosis methods. Asim et al. identified Robertsonian translocations and isochromosomes (separation of two long arms) as other causes of the syndrome apart from the presence of an additional chromosome 21 in infants. The abnormal chromosomal numbers result in overexpression of genes based on the gene-dosage-imbalance theory. Other theories related to the disorder include the amplified developmental instability hypothesis, which is similar to the gene-dosage-imbalance theory, and critical region hypothesis that identifies the Down syndrome critical regions as responsible for the phenotypic manifestation of the disorder. Diagnostic methods discussed include karyotyping and rapid aneuploidy testing methods for diagnosis prenatal samples. The team makes recommendations for management of the disease emphasizing on an organized multidisciplinary approach where multiple specialists work together to monitor and manage the patients.
Letourneau A., et al. (2014) Domains of genome-wide gene expression dysregulation in Down’s syndrome. Nature 508, 345-350
Letourneau et al. studied the transcriptome (all messenger RNA molecules) of fetal fibroblasts from maternal twins to assess the extent of gene expression in Down’s syndrome. The group showed the difference in expression in the domains as either up-regulated (excess) or down-regulated (insufficient) which were preserved in the stem cell line from the twins’ fibroblast. These gene expression dysregulation domains (GEDDs) associate with lamina-associated domains (LADs) and replications domains but only the GEDs underwent modification similar to that of the H3K4me3 profile the affected fibroblasts. The results show that the chromatin environment in the nucleus is subject to change affecting the messenger RNA, which are responsible for cell activities, and thus GEDs affect some of the disorder phenotypes.
Kirsammer G. & Crispino D. J. (2016). Signaling a link between interferon and the traits of Down syndrome. eLife insight 1-3
Kirsammer and Crispino claim that Down’s syndrome is among the most complex genetic disorders that affect humans. It occurs averagely in 1 out of 700 infants in North America and Alexander et al. suggest that it presents with heart defects, Alzheimer’s disease, receptiveness to leukemia, intellectual disability, and a reduced possibility of developing additional tumors. Down’s is the result of the presence of an additional copy of chromosome 21 in several or all cells. Sullivan et al., through the sequencing RNA from human fibroblast tissue taken from individuals who have Down’s, demonstrate that the cells have 50 percent more genetic product of chromosome 21 than normal tissue. In addition, they revealed that the pattern of gene expression was consistent in affected cells associating with interferon-stimulation for a transcriptional response. From their study, Sullivan was able to demonstrate that affected cells active interferon pathways, the gene that becomes active is specific to cell types allowing them to determine that the traits of the syndrome are a result of the additional chromosome. The study allowed the team to provide useful data regarding the contribution of interferons in the manifestation of clinical characteristics of Down’s and how targeting these interferons can develop treatment solutions.
Jiang J et al. (2013) Translating dosage compensation to trisomy 21. Nature 500, 296-300
Jiang and her colleges, using the concept of Barr bodies found in female cells, attempted to inactivate the additional chromosome 21 in stem cells and succeeded. Through gene splicing and editing, they inserted an inducible transgene, XIST (the X-inactivation gene), on the arm of the additional chromosome. The transgene resulted in the stable modification, transcription, and DNA methylization to form a ‘chromosome 21 Barr body’. In addition, they were able to control the expression of individual genes including chromosome 21 by inserting a genetic switch that they manipulated using doxycycline. The study is a step in identifying the cellular processes necessary for auto correction of the disorder and development of target-specific treatments for the disorder.
Rezayat A. A., Nazarabadi M.H., Arabili M. H., Shokri M, Mirzae S, et al. (2013) Down Syndrome and Consanguinity. Journal of Research Medical Sciences. 995-997
Rezayat AA et al. conducted a study to investigate the frequency of maternal kinship and age and its correlation with Down syndrome as a previous study suggested there is no association of Down syndrome with consanguinity. The study of amniotic fluid of a pregnant woman has been the primary criteria for prenatal identification of chromosomal defects, but other diagnosis methods were introduced leading to the emergence of screening markers. There were 38 patients involved in the study and parental details and familial relationships recorded resulting in two groups: Consanguine and non-consanguine marriages. The study revealed a range of chromosomal defects such as trisomy and double aneuploidy among others. The consanguine marriage group demonstrated complete trisomy status while the non-consanguine marriage group had 88.9 percent. The use of Fisher’s Exact test showed that the chromosomal status of the subject was not dependent on consanguine marriage as well as the age of the mother.