Down syndrome (DS) is a genetic disorder, occurring when an individual has all or part of an extra copy of chromosome 21 (Trisomy 21). The following will address fundamental genetics of DS and various mechanisms by which it occurs such as nondisjunction, translocation, and mosaicism, and the impact of the current COVID-19 pandemic has on DS patients with special emphasis on the role of immune dysregulation.
Background and History
DS is the most common genomic syndrome of intellectual disability and is characterized by variable clinical symptoms. The term “genetic disorder” can be misinterpreted as a condition that is inherited, however DS is not typically inherited.
Major clinical features of DS are up-slanted palpebral fissures, a flat nasal bridge, nuchal folds, clinodactyly of the fifth finger, and single palmar flexion crease. There is a myriad of medical conditions that are common in DS and need careful monitoring. These include, but are not limited to, cardiac complications, neurodevelopmental issues, auto-immune disorders, hearing deficits, sleep disorders, and predisposition to certain cancers (transient abnormal myelopoiesis).
Genetics of Down Syndrome
An extra copy of either the whole chromosome 21 or partial segment can be caused by four mechanisms. Chromosome 21 encodes more than 650 genes. These genes, along with epigenetic factors, all contribute to the DS phenotype due to the effects of overexpression of the involved genes.
The four mechanisms by which DS occurs are:
- Meiotic nondisjunction: This occurs in about 96 percent of all cases. This is due to an error in the meiotic cell division when the egg or the sperm was formed. This results in the abnormal cell with 24 chromosomes, instead of the usual 23. At fertilization, the zygote has 47 total chromosomes with a third copy of chromosome 21.
- Translocation: This mechanism is much rarer and accountsfor 3 – 4 percent of all DS. In this situation, in addition to two normal chromosome copies of 21, either a complete third copy or part of chromosome 21 could be attached to another chromosome. Translocation type DS cases can only be reliably diagnosed by karyotype analyses. Identification of this particular mechanism is essential for genetic counseling for family planning.
- Mosaicism: In this infrequent mechanism, DS individuals have a mixture of some cells with extra copy of chromosome 21 and some with normal two copies. The clinical findings in these individuals vary widely. Fluorescence-in-situ hybridization (FISH) based testing on more than one tissue type (blood and buccal cells) and on more than the standard number of cells analyzed is highly recommended to determine mosaicism.
- Partial trisomy: This is very rare, seen in less than 1 percent of DS cases, and refers to duplication of a particular segment of chromosome 21.
Diagnostic Testing in Down Syndrome: Prenatal & Postnatal
Along with conventional methods of maternal serum analysis and ultrasonography, non-invasive screening of fetal cell-free DNA in maternal plasma has now become a routine approach for screening. Although the sensitivity and specificity is high using this screening method, cytogenetic analysis (karyotype), FlSH, and Chromosomal Microarray Analysis (CMA) on fetal cells obtained by amniocentesis and chorionic villus sampling is the gold standard for a definitive diagnostic test.
Upon clinical suspicion of an infant with DS, the most definitive diagnostic tests are through cytogenetic testing by conventional karyotype, FISH, or CMA.
Impact of the Global SARS-CoV-2 Pandemic on Down Syndrome
Individuals with DS have documented immune disbalance, which leads to chronic immune dysregulation. There is an increased incidence of autoimmune disorders, inborn defects in thymic function, chronic inflammation, hyperactive interferon activity, and the ensuing disbalance in T and B cell development.
Due to the extra copy of chromosome 21, there is triplication of four interferon receptors that lead to overexpression and heightened immune activity in individuals with DS. Although it is not yet known what impact of this immune dysregulation in DS will have when infected with SARS-CoV-2, it is plausible that it may result in an exaggerated cytokine release (cytokine storm). This possibility of severe response suggests that individuals with DS affected by COVID-19 should undergo careful and repeated monitoring of pro-inflammatory markers and be aggressively treated with a regimen to slow down the over-reactivity of cytokines.
With the significant progress in understanding the clinical features, genetics, and medical issues of DS, the life expectancy of individuals with the condition have improved. An important goals of healthcare providers are to improve the quality of life and completely resolve symptoms in DS. A careful multi-disciplinary team is needed to provide integrative medical care and support to individuals with DS.
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