The Genetic Perspective of Down Syndrome, Health News, ET HealthWorld

by Dr Firoz Ahmad

Down syndrome (DS) is a birth defect caused by the presence of an extra copy of chromosome 21 and is the most common chromosomal abnormality in humans. It occurs in about 1 in 800 births globally and in India, DS accounts for nearly 23,000 to 29,000 live births per year. The original account of the syndrome, in 1866, was attributed to an English physician John Langdon Down, but its association with chromosome 21 was deciphered almost 100 years later, and the condition was named “Down syndrome”. Children born with DS are associated with intellectual disability and developmental delays, and are at increased risk of developing a number of comorbidities such as endocrine problems, subfertility, recurrent respiratory infections, heart defects , dementia, obesity, leukemia and hearing/sight problems. Most of the time, DS is not hereditary and is often caused by an error in cell division during early fetal development. There are basically 3 types of Down syndrome. Most people with the disease have a regular extra chromosome 21 (+21, ≈94%), while a smaller number have a translocation in which extra material from chromosome 21 is attached to another chromosome, rather than to be a separate chromosome 21 (≈4%); or mosaic Down syndrome – in which there is a mixture of normal cells and abnormal cells with an extra chromosome 21 (≈2%). Advanced maternal age, parents who carry the DS genetic translocation, and parents who have a child with DS are at increased risk of having another child with Down syndrome.

Large-scale studies combined with functional cytogenetic and genomic testing suggest that DS is most likely due to an aberrant gene dosage, in this case from three doses of genes from chromosome 21. The 200 to 300 genes present on chromosome 21, as well as epigenetic factors, have been identified as contributors to the clinical features of the syndrome. Overexpression of these genes causes significant disruptions in abnormal protein expression, affecting the development and function of most organs and organ systems.

DS has considerable implications in terms of health costs, given the individual and socio-economic consequences. Although there is no way to prevent it, it can be detected early in pregnancy through screening and diagnostic tests. The screening test is usually a combination of a blood test, which measures the amount of various informative biomarkers in the mother’s blood (eg, AFP, Dual Screen, Quad-screen). This helps identify the risk of carrying a baby with DS, by combining information about maternal age, ultrasound measurements, and serum test results. One of the major drawbacks of the screening test is its limited sensitivity and specificity for detecting chromosomal abnormalities (≈50% and 85-90% respectively). Thus, high-risk serum screening tests are often offered invasive procedures to examine chorionic villus sampling (CVS), amniocentesis, or fetal DNA from the placenta for definitive genetic diagnosis using conventional cytogenic analysis. and/or by rapid genomic testing – FISH (fluorescent in situ hybridization), QF-PCR (quantitative fluorescence PCR) and MLPA (multiplex probe ligation assay). These diagnostic tests look for changes in the chromosomes that would indicate a diagnosis of DS up to 12 to 18 weeks gestation. Unfortunately, invasive testing carries a small but significant risk of miscarriage of around 1%, which often limits its acceptability in a fraction of women. Thanks to recent technological advances in high-throughput genomics that have allowed us to decode fetal cell-free DNA sequence (cfDNA) from maternal plasma using the next-generation sequencing (NGS) approach. With the introduction of the first non-invasive prenatal genetic test (NIPT) for the detection of fetal chromosomal aneuploidies in clinical practice in 2011, in no time NIPT became the real game changer across the world and bought a complete paradigm shift in the approach to prenatal screening for DS. Several studies have shown that NIPT is more effective than routine screening in detecting DS (from 10e week of pregnancy) in women in the high-risk group. Interestingly, NIPT produces fewer false positives and higher positive predictive values ​​than serum screening. The high specificity of NIPT for detecting DS (99.7%) is valuable for a parent carrying a translocation and for a woman at increased risk of having an affected fetus. Notably, the American College of Obstetricians and Gynecologists (ACOG) released a new set of guidelines in 2020, recommending that prenatal aneuploidy screening (NIPT) be offered to all pregnant women, regardless of age or other risk factors.

Given the complexity of the high-end NIPT test, it is important to note that the presence of a sufficient amount of fetal cell-free DNA in the mother’s blood (fetal fraction) is essential and critical for a reliable result. Generally, the fetal fraction should be above 4%, which usually occurs after the 10e week of pregnancy. The NIPT test must include a reliable algorithm to correctly quantify the fetal fraction, as low fetal fractions can lead to an inability to perform the test or a false negative result. Reasons for low fetal fractions include testing too early (before 10e week) during pregnancy, improper sample collection, maternal obesity and fetal abnormality. The affordability, quick turnaround time and availability of genetic counseling (pre and post-test) can play an important role in its acceptability by the masses.

There is no specific treatment for Down syndrome; however, early interventions can certainly improve functional outcomes. First and foremost, the family should be counseled for different possible conditions associated with DS, which will help in prompt management of the child. The intervention of the physiotherapy, occupational therapy and speech therapy teams will be of immense help. Most importantly, any child with Down syndrome should receive both psychological and educational support. With ongoing global research, we can speculate on treating aspects of DS pathology, or even completely improving the DS phenotype, for example using gene therapy or silencing extra chromosome 21 function.

Dr Firoz Ahmad, Section Head – Molecular Pathology, SRL Diagnostics, Mumbai.

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