Clinical Genetics Question and Answers

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Question 1.

Major molecules and mechanism of action of the therapeutic agent

Using an RNA-centered molecular approach to therapy largely involves silencing or the suppression of post-transcriptional gene expression. Molecules used in this method include antisense oligonucleotide (ASO), microRNAs (miRNAs) and small RNAs (siRNAs). They perform their actions by binding to selected messenger RNA (mRNA) sequences in order to degenerate or to block the translation process.

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siRNAs are shortened, double-stranded RNA molecules, which are to be compatible with the mRNA of a target gene. After entering the cell, they get integrated into the RNA-induced silencing complex (RISC) (Oprea, and Hasselgren, 2017). The complex stays with one strand of the siRNA and gets directed to the complementary mRNA. RISC would then cleave the mRNA resulting in degradation and inhibiting translation into protein. This is a very specific and efficient process of silencing the genes.

Clinical Genetics Question and Answers

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miRNAs occur naturally and are RNA molecules that have a regulatory effect on expression of genes by imperfectly matching with target mRNAs. Such a binding usually leads to transcriptional repression as opposed to total degradation (Diener et al. 2023). Although they are all natural and normal processes of gene regulation, synthetic miRNAs can be introduced in therapy to adjust the disease-related genes.

ASOs are unimolecular single-strand DNA or RNA and match by base pairing with target mRNA. They may directly inhibit translation or alternatively may enlist RNase H, an enzyme that cleaves the RNA half of an RNA-DNA hybrid. ASOs do not need to be integrated into the RISC complex as compared to siRNAs and miRNAs.

All these strategies are directed to the attainment of less or inhibited synthesis of disease related proteins. To give an example, such genes as names of genetic disorders, cancer and viral infections were attacked by implementing siRNA therapies (Origene, 2023). The specificity and the specific mechanism of base pairing and degradation makes the process of gene suppression efficient and selective.

Their clinical use motifs

There are quite a number of issues to consider with regard to application of therapies targeting RNA in clinical practice. Delivery forms a major challenge, whereby the RNA molecules are very unstable and can easily be destroyed by the blood nucleases (Mihaela Hostiuc et al. 2024). As a solution, chemical alterations and carrier vehicles such as lipid nanoparticles are used to increase stability and uptake by the cells.

The other issue is generalized effects and there is the possibility of non-specific binding causing unwanted silencing of genes. Such a risk requires the use of design of the sequences, as well as preclinical testing. Critical also is the immune response, because synthetic RNAs can activate the inflammation pathways, particularly through toll-like receptors.

Lastly, therapeutic window and duration of action need to be maximized so that enough efficacy with no toxicity is maintained. Strict evidence of safety, specificity and uniformity in production has to be shown when getting regulatory approval (Lista, and Sirimaturos, 2021). Nevertheless, RNA-based treatments are a potential route of precision medicines, despite the mentioned challenges.

Figure 1: siRNA or antisense oligonucleotide action

(Source: Created using Draw.io)

Question 2.

Gene recognition of the highly up and down regulated genes

The x-axis of the given volcano plot between the gene expression of breast cancer patients and that of controls is the log 2 fold change and the y-axis -log 10 p-value. Those genes that are on the right are upregulated and those on the left downregulated. The vertical dotted lines identify the cut off of log2 to show the log2 fold change, and the horizontal line is significant cut- off.

Based on labelled genes in the plot, majorly, some of the upregulated genes are CDCA8, KIF2C, CDC20 and CDCA2 (Gu et al. 2024). These genes are found on the extreme right side of the plot and this depicts that they have high expression in the breast cancer tissue as compared to normal. Considerably downregulated genes are CST9, ACSM1, FOXA1, C1orf64, MLPH and PRR15 that are placed on the far left side of the graph, which means that they are less expressed in cancer tissue (Google, 2016). PRR15 and MLPH are still within the significant region at a closer distance to the centre since they possess p-values and fold changes.

Genes and their role in pathophysiology of breast cancer

CDC20 is one of the important genes greatly upregulated, which is involved in cell cycle progression. It also triggers the anaphase-promoting complex/cyclosome (APC/C) which is an important E3 ubiquitin ligase that catalyzes metaphase to anaphase transition in mitosis. CDC20 overexpression is well documented in many types of cancer, including breast cancer (Mehta et al. 2024). It causes hyper proliferation and aberrant changes in the cell cycle, increasing the speed of cell division and scarring chromosomal errors, favoring tumour progression and adverse prognosis. The increased CDC20 expression has been associated with high-grade of tumours and short survival time in breast cancer, which establishes its status as an oncogenic driver.

Conversely, a strongly downregulated gene namely FOXA1 is a transcription factor which participates in the regulation of hormone responsive genes. It plays a critical role in the estrogen receptor (ER)-positive breast cancers wherein it allows chromatin access to the estrogen receptor complex (Yuan et al. 2024). Altered expression of FOXA1 has been linked to presence of basal-like or triple-negative breast cancers that have no hormone receptor expression, and which are later characterized by aggressive clinical behaviour. Its downregulation has potentially led to the de-differentiation of the epithelial cells and the augmented proliferation, which are the hallmarks of these subtypes.

Cumulatively, the uncontrolled activity of such genes as CDC20 and FOXA1 indicates the heterogeneity of breast cancer at the molecular level. Increasing mitotic control factors and decreasing hormone-binding transcription factors promote uncontrolled growth, hormone-independent cell growth and development of more aggressive tumour bullshit (Pei et al. 2023). These changes not only contribute to the characterisation of the disease but the information can be used in potential targeting of therapies.

Figure 2: Volcano plot showing breast cancer tissue vs healthy tissue

(Source: Provided)

Question 3.

Interpretation of Pedigrees and ethics

In Figure 3, the pedigree demonstrates an autosomal dominant type of inheritance in line with Huntington Disease (HD). Individual III.5, the proband, has a heterozygous CAG repeat expansion of the gene variant (28/41), meaning that the person has one normal allele and one expanded. Other affected members in generation II also have expanded alleles (II,6: 17/43) (Caron et al. 2020). The individuals belonging to generation III, e.g. III.1 (23/48) have longer repeat expansions, generally leading to an earlier onset as is the case with genetic anticipation.

Analysis of the pedigree shows several people at risk. Since HD is dominant, every child born of an affected parent has a possibility of 50 percent of inheriting the defect. This brings a number of ethical issues about genetic status disclosure between families. A reverence of autonomy is important. Gene disclosure could be beneficial to at-risk relatives with regards to making informed life and reproductive choices, yet some people might not want to know about their genetic condition (Phillips et al. 2021). In order to do so, non-directive genetic counselling is required to facilitate informed and voluntary decision-making.

There is some element of ethical intricacy in predictive testing, especially where the individual does not have any symptoms. The genetic risk is psychologically burdening and can also cause discrimination in either employment or insurance (Chapman et al. 2019). The disclosure to non-at-risk relatives including partners or in-laws should also be done cautiously but the confidentiality must be taken into account and reproductive consequences to their child should also be taken into account.

Predicative test and clinical method

Predictive testing with minors is not seen to be recommended with late onset diseases such as HD. Half of the world is filled with scientific principles that prove that some type of preventive or therapeutic intervention is possible during childhood, testing is suitable: but that is not true of HD (Hercher, 2019). When a minor is tested, they are denied a chance to make the future choice and can suffer psychological damage in the case when no assistance is possible. However, young adults can want to be tested to make a choice about reproduction or career. In such instances, pre and post-test counselling is essential in measuring the level of preparedness and mental health.

The leading question in relation to HD families is reproductive decision-making. A positive individual will weigh the available options such as preimplantation genetic diagnosis (PGD) or prenatal diagnosis so that they do not contend with the mutation (Molina, 2022). Some of them can opt to stay child-free or undergo gamete donation. These decisions might be morally and emotionally demanding. They require clinical geneticists to support and present all reproductive options in an un-threatening and neutral way that respects the cultural, personal, or family values.

The psychological effect of predictive testing and diagnosis should not be miscalculated. Frequent are anxiety, survivor guilt and changed family dynamics (Oliveri et al. 2018). Continued psychological intercession, such as evacuation to support associations and psychological care experts, is an important part of compassion. When handling HD in clinical situations, a humanistic mind, a moral approach as well as a patient-centred approach are important ways of going about the management.

Figure 3: Pedigree showing family discovered to present with Huntington ’s disease

(Source: Provided)

Question 4.

The suggested treatment plan, benefits and weaknesses

In a patient of metastatic colorectal cancer (mCRC) that is resistant to irinotecan-based chemotherapy, it is advisable to go in with a personalized regimen that includes either the cetuximab or panitumumab treatment (Morris et al. 2022). They are monoclonal antibodies which exhibit high specificity in binding to the extracellular domain of epidermal growth factor receptor (EGFR) to prevent downward signalling pathways facilitating tumor growth and proliferation.

Specifically, cetuximab is usually combined with irinotecan when earlier irinotecan based regimens have failed. Such a mixture could sensitize tumors to irinotecan. Alternatively, there is an alternative of having panitumumab monotherapy in the instances where the combination therapy is not tolerated. The key benefit of this method is also in the mechanism of action that operates directly on the EGFR pathway and, thus, has the aspect of specificity that is not shown by regular chemotherapies (Shah, and Lester, 2020). The research results demonstrated a better progression-free survival in the correctly chosen patients who were treated by anti-EGFR medications.

Nonetheless, there are restrictions of these therapies. They only efficacy against patients that are not stained with mutations of the KRAS or NRAS genes, which are downstream of EGFR in the signalling pathology. Changes that occur in these genes result in the permanent activation of the pathway making EGFR blockade ineffective. Side effects may also be severe, as follows: skin rash, hypomagnesemia, and infusion related reactions (Wu et al. 2023). Moreover, other than advancing progression-free survival, the effects of these treatments on overall survival are usually low. Resistance can also emerge after some period, on account of secondary mutation or activation of alternative pathway e.g. MET or HER2 amplification.

Other genetic factors or markers

It is crucial to evaluate the KRAS and NRAS mutation prior to starting the anti-EGFR therapy. These targeted therapies are only restricted to patients with wild-type alleles. Mutations in exon 2, 3 or 4 of either of these genes are linked to resistance and thus the use of the same can be disregarded (Xia et al. 2025). Molecular screening has already become the norm in the treatment of mCRC.

The other biomarkers are BRAF V600E mutations that are also associated with poor prognosis and resistance to EGFR inhibitors. It can be assumed that patients with BRAF-mutated tumors can enjoy the benefits of combination therapy that includes BRAF inhibitors, MEK inhibitors, and EGFR blockers. The microsatellite instability (MSI) status ought also to be determined. The immune checkpoint inhibitors such as pembrolizumab may be more effective in MSI-high tumors.

Lastly, HER2 amplification and PIK3CA mutations are evolving markers which, potentially, may determine the use of studies, treatments or participation in the clinical trial (Rasti et al. 2022). By determining these genetic changes, it is possible to provide the patient with more comprehensive and personalized treatment, and the chance of clinical impact is greater, and the unnecessary toxicity is reduced.

Reference List

Journals

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