Scientific Literary Review Essay Example

1 CHARGE Syndrome’s Area of Research and Study Wesley Beals Biology 190L: Introduction to Organismal Biology Lab Section 3901 Professor Meghan Rodela Abstract CHARGE syndrome is a rare genetic disease that causes multiple problems throughout the body. One of the genetic variations of CHARGE and the most common mutation that causes it is a mutation in the CHD7 gene that helps regulate gene expression in early development. Although better understood than when it was first described in the 1970s, many things about CHARGE are still not fully understood and many of these are unknown areas of research. Each of these research teams sought understanding in different areas. A team at the University of Washington School of Medicine researched the effects of a CHD7 knockout on mice. A team of doctors at the Boston Children's Hospital for Harvard Medical School studied and put quantitative data forward on the study of CHARGE. Lastly researchers in Milan, Italy analyzed the process of diagnosis for those with CHARGE as they sought to better the diagnosis of CHARGE in newborn. Each of these areas of study are helping advance the understanding of the syndrome and despite many challenges, such as low sample size, they provide valuable insight and open new areas of study and inquiry. 2 Start of Paper CHARGE syndrome, also known as Hall-Hitner syndrome, is a rare genetic disorder, which occurs in about .0001 percent of live births, which affects various systems throughout the body (Bedeschi et al., 2020). This syndrome is called CHARGE because CHARGE is an acronym for each of the major symptoms of the disorder which include: coloboma or missing eye tissue, heart defects, atresia of the choanae or blockage in the nasal passages, retardation, genital abnormalities, and ear abnormalities (Zhoulideh & Joolideh, 2023). Among the major symptoms of this syndrome are many other miscellaneous symptoms that can include but are not limited to kidney problems, developmental delays, cleft lip and palate, facial anomalies, and many others (Zhoulideh & Joolideh, 2023). Of the babies that are born with CHARGE, there is a wide range of conditions that range from very mild to life-threatening, and the variance in the symptoms can sometimes make it challenging to get a completely accurate diagnosis for these babies (Bedeschi et al., 2020). On top of this variance in symptoms, CHARGE is known to have a lot of symptoms that overlap with many other genetic conditions like Kallmann syndrome, DiGeorge syndrome, 22q11.2 deletion syndrome, and many others which further increases the complication of diagnosis (Zhoulideh & Joolideh, 2023). In addition, although the syndrome is better understood than when the syndrome was first described in the late 1970s, the syndrome and how these different symptoms manifest is still not well understood (Bedeschi et al., 2020). One of the major strides in understanding CHARGE in the last 50 years is the main genetic cause for this syndrome. This syndrome is caused by a mutation in a gene on chromosome eight that codes for a protein known as Chromodomain Helicase DNA binding protein 7 or CHD7 (Peng et al., 2023). This protein controls the regulation of gene expression and is critical in the early developmental stages of life (Peng et al., 2023). In addition, a smaller percentage of cases of 3 CHARGE are caused by a mutation of the gene for the protein Semaphornin-3E (Zhoulideh & Joolideh, 2023). Despite understanding the underlying genetic cause of CHARGE, many areas of the syndrome require more study and testing particularly the areas of how the CHD7 manifests the symptoms, having actual quantitative data for the syndrome, and increasing the accuracy of early diagnosis. To better understand the effects of the CHD7 on development, a research team sought to study the effect of the protein and its absence in mice. In their experiments, these scientists from the Washington University School of Medicine sought to answer how the CHD7 affects gene expression and how that would further go and hinder the development of the cerebellum and other areas of the brain (Reddy et al., 2021). They then compared these effects in gene expression to human fetal tissue and saw if the CHD7 does similar things in both species (Reddy et al., 2021). To answer these questions, these scientists sampled the mice pups from the same litter and kept them under the same conditions and ran them both through the same tests (Reddy et al., 2021). The experimental group of mice had their CHD7 gene disabled, leading to a similar effect like CHARGE, and their control group, which did not have the gene disabled, had a similar age and sex breakdown as the experimental group (Reddy et al., 2021). The mice were then analyzed often so that the scientists could measure the expression of certain genes and analyzed the mice’s brains to see the differences (Reddy et al., 2021). After the tests and analysis, the scientists noticed a few things. One was that there was a massive difference in the expression of certain genes between the two groups like they predicted (Reddy et al., 2021). They noticed that through the knockout of the CHD7 gene that cells that would later develop into granule cells in the cerebellum area were underdeveloped and that these cells were unable to express the genes needed to develop into mature granule cells (Reddy et al., 2021). This would then further lead to 4 an underdeveloped cerebellum. In addition, they also noticed that through disabling of the CHD7 gene, brain folding was different between the two (Reddy et al., 2021). The experimental group had increased brain folding in areas where it was smooth in the control (Reddy et al., 2021). These two things led to impaired brain function in the experimental mice compared to their littermates (Reddy et al., 2021). After testing the mice, the team decided to compare the CHD7 effect on gene expression and the types of genes affected by CHD7 between humans and mice (Reddy et al., 2021). They found in their analysis that there is about 60% similarity in the genes that CHD7 regulates between the two species (Reddy et al., 2021). Through these findings, they concluded how some of the symptoms of CHARGE come about and about how the expression of these genes or lack thereof leads to changes in brain development. In addition to the studies done by the University of Washington on mice, a team from the Boston Children’s Hospital for Harvard’s Medical School studied and collected quantitative data on the structure of the brain in patients with CHARGE. The team had noticed a lack of quantitative research on CHARGE brains and sought to be the first to provide data on the subject compared to normal brains (Tadashi et al., 2019). With that goal in mind, the researchers gathered their sample for their CHARGE study from the medical records of patients treated at the Boston Children’s Hospital and then for their control group they sampled from a medical database of people who were comparable in age and gender and did not have any major neurological problems (Tadashi et al., 2019). The scientists then ran all the participants through the same MRI machine to get a structural MRI as well as some HARDI tractography (Tadashi et al., 2019). After taking these measurements, the researchers ran the data through a series of statistical tests to help show that their data could be a plausible representation of the overall population (Tadashi al., 2019). When the scientist compiled the results, the results were what was 5 expected (Tadashi et al., 2019). Qualitatively, all the CHARGE patients matched the major criteria for CHARGE and as a result, the MRI’s showed some differences in the brain between the two groups such as missing olfactory nerves used in smell, underdevelopment in areas of the cerebellum, and many other such other underdeveloped parts of the brain (Tadashi et al., 2019). Upon analysis of the quantitative data, they noticed, through the MRIs, that there were significant volume differences in the brain tissues. They found differences like the volume of white matter in the brain in CHARGE patients compared to normal patients was 419,852mm3 to 482,119mm3 (Tadashi et al., 2019). Other areas such as the grey matter in the top of the brain and lower parts of the brain were different, with CHARGE to normal being measured as 564,306 mm3 to 584,210 mm3 and 36,365 mm3 and 36,798 mm3 respectively (Tadashi et al., 2019). The researchers also noticed that the right cortex of the brain was thicker in those with CHARGE than without it as 3.01 mm to 2.79 mm but noticed no statistical difference in the left cortex’s thickness with 2.84 mm to 2.79 mm (Tadashi et al., 2019). With each of these measurements taken, the researchers turned their attention to the HARDI images. The researchers found many of the same things that they found in the basic MRI but also found that many fibers in the brain that were longer and thinner in CHARGE brains than in normal brains (Tadashi et al., 2019). With these observations and measurements, the team came to better understand how this asymmetrical development in the brain could be a possible reason for an asymmetrical face found in many people who have CHARGE (Tadashi et al., 2019). In addition, these measurements and observations open further questions and study about brain development with CHARGE and increased the quantitative understanding of the syndrome. Last of the areas of constant study and research of this syndrome is the area of diagnosis and research from a team in Italy has found some better ways for diagnosis. This team of 6 neonatal doctors wanted to better the diagnostic process of CHARGE and provide key areas, to look for CHARGE that could help lead to better and quicker diagnoses (Bedeschi et al., 2020). This team took a sample of eight patients from a local hospital in Milan, Italy (Bedeschi et al., 2020). Each of these patients was diagnosed with CHARGE and went through many tests such as MRI’s, CT scans, auditory tests, ear, nose, and throat evaluations, neurological and genetic tests to reach their diagnosis (Bedeschi et al., 2020). Through looking through the medical records and test results of each of the patients the researchers noticed common patterns with the syndrome (Bedeschi et al., 2020). They found variety in the way the syndrome manifested and with each of the patients they found that they each had a vastly different process to reach the CHARGE diagnosis (Bedeschi et al., 2020). Of the eight patients, patient four was the only patient to manifest all eight of the major features of the disorder and was diagnosed shortly after birth (Bedeschi et al., 2020). Of the other patients, patients 1-3 and 5-7 were all diagnosed within a month of birth but had variation in the symptoms that made it difficult to diagnose (Bedeschi et al., 2020). After each received a CT scan and other evaluations, they were finally diagnosed (Bedeschi et al., 2020). The odd case of the eight was patient eight because they were not diagnosed until they were 18 months and the diagnosis for eight was complicated (Bedeschi et al., 2020). Patient eight did not manifest very many symptoms and as a result, while CHARGE was considered, there were many other syndromes that were considered before it (Bedeschi et al., 2020). Through many tests and evaluation, each of the other options were ruled out and only after noticing that patient eight’s ears were unusually shaped, like one of the primary features of CHARGE, was when they were diagnosed with CHARGE (Bedeschi et al., 2020). Through the research into each of these patients, the researchers found that one of the increasingly helpful tools for diagnosis was looking at the structure of the ears because in their estimates more than 7 nine out of ten patients with the syndrome had ear issues (Bedeschi et al., 2020). While diagnosis is still quite challenging, research into better diagnostic methods helps doctors and researchers better understand CHARGE. The research into CHARGE syndrome has allowed for increased understanding in the areas of how CHD7 manifests some of the symptoms of CHARGE, some of the quantitative data for CHARGE, and some better diagnostic methods for determining CHARGE. While each of these studies and experiments have allowed for increased understanding, there are limitations on the studies themselves. Each study, while performed with precision and careful calculation, struggled with a small sample size on each experiment. The team at the University of Washington only had a maximum sample size of fifteen mice in both their control group and experimental group, and only compared gene expression data with only one sample of fetal tissue (Reddy et al., 2021). The team from Boston had only ten patients with CHARGE and twenty control patients (Tadashi et al., 2019). Lastly, the researchers in Italy only pull their sample from eight patients (Bedeschi et al., 2020). With each of these small samples, there are limits to the number of conclusions that can be made regarding CHARGE but each of them acknowledges that the samples were small but to make up for it, they went did thorough testing and did significant statistical analysis to all their data (Tadashi et al., 2019; Bedeschi et al., 2020; Reddy et al., 2021). Even with their small sample size, they were able to better understand CHARGE. Lots of unknowns remain about CHARGE and many things still need to be studied things such as, how does CHD7 affect gene expression in other parts of the body outside the brain, what are some other useful measurements that can help doctors in diagnosis, and lastly, what are possible way to catch CHARGE while babies are in utero. With each of these areas of 8 research scientists are gaining a better understanding of how to best help people with CHARGE and further understand the underlying mechanisms of genetic disease.