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Disease Diagnosis Using Non-NGS Techniques and Whole Genome Illumina Sequencing

Next generation sequencing (NGS), also known as high-throughput sequencing involves different types of modern sequencing technologies such as Illumina, Roche 545, Ion torrent and SOLiD sequencing. These techniques sequence DNA and RNA much more rapidly and efficiently than first generation sequencing (Sanger) and has therefore revolutionised the study of genomics and molecular biology. This essay focuses on three different diseases, Cystic Fibrosis (CF), Huntington’s disease (HD) and Charcot-Marie-Tooth Disease (CMTD), and how they can be diagnosed using both non-NGS techniques and whole genome Illumina sequencing. Thereafter, the advantages and limitations of using RNA-sequencing in a patient with congenital muscular dystrophy will be discussed.
Cystic Fibrosis molecular cause
Cystic fibrosis is the most common autosomal recessive disease in Caucasians and affects around 1 in 2,500 individuals (1). It is caused by the mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), and the most common mutation is the deletion of three-nucleotides causing a loss of a phenylalanine residue at the amino acid position 508 (?F508) (1).
The CFTR protein is a cyclic adenosine monophosphate (c-AMP) dependent channel that works as an electrostatic attractant by outlining intracellular and extracellular anions toward the positively charged transmembrane (TM) domains inside the channel (2). Two TMs form a chloride channel pore, allowing chloride and bicarbonate transportation (2). Normally, when CFTR is activated, the chloride ions are secreted out of the cell as epithelial sodium channels are inhibited. This leads to water leaving the cell through osmosis, providing fluid for epithelial tissue secretions (1).

In CF patients, the combination of loss of chloride secretion and sodium hyper-absorption via the epithelia sodium channel results in loss of airway surface secretions. This effects the overlying mucous becoming adherent to the airway cells and preventing effective ciliary activity (2). Thus, the inhaled bacteria are no longer cleared but instead set up low grade persistent infection where the associated inflammatory and immune responses lead to airway damage and airways obstruction due to the increased concentration of salt in sweat (2).
Huntington’s Disease molecular cause
Huntington’s disease is an autosomal dominant and late-onset neurodegenerative disorder that affects 5-10 out of 100,000 individuals (3). It is caused by a CAG trinucleotide repeat expansion (>35 repeats) in the IT15 gene that results in a long stretch of polyglutamine protein close to the amino terminus of the huntingtin gene (HTT) (4).
One of the hallmarks of HD is the formation of cytoplasmic aggregates and nuclear presences throughout the brain (4). Polyglutamine inclusions contain highly ordered amyloid fibres with high ?-sheet content and low detergent solubility that sequester numerous other proteins, including factors that are important for transcription and protein quality control. This suggests that the presence of polyglutamine has an impact on the cellular function and contributes to a complex loss-of-function phenotype (4). This leads to an inherited neurological illness causing involuntary movements, severe emotional disturbance and cognitive decline (3).
Charcot-Marie-Tooth disease (CMTD) molecular cause
The hereditary motor and sensory neuropathy, also known as CMTD is the most common inherited neuromuscular disorder affecting at least 1 in 2,500 (5). The inheritance of CMT can be autosomal dominant, autosomal recessive, or X linked (5). Mutations leading to CMT are grouped into demyelinating, axonal and intermediate forms that are based on electrophysiological and pathological findings.
The demyelinating types are characterised by severely reduced motor nerve conduction velocities (MNCVs) and mainly by myelin abnormalities (5). The majority of people with CMTD show a predominantly demyelinating peripheral neuropathy and are classified as CMT1. CMT1A is a subtype that is associated with an autosomal dominant duplication on the peripheral myelin protein 22 gene (PMP22) and is expressed in the compact myelin of Schwann cells of the peripheral nervous system (6). Thus, CMT is mainly characterised by distal muscle weakness and atrophy leading to motor handicap (5).
Cystic Fibrosis diagnostic tests
As CF is a complex genetic disease in which mutations in the CFTR gene alter the function of the anion channel that leads to an increased concentration of salt in sweat. The sweat secretions can be stimulated either through cholinergic or ?-adrenergic pathways. The cholinergic pathway is important for normal thermoregulation and is not affected in CF patients. However, the ?-adrenergic pathway is either absent or markedly reduced in CF patients that can be measured using a non-NGS technique called sweat chloride concentration. Other non-NGS techniques include abnormalities of an ion transport in respiratory epithelia of patients with CF that are associated with a different pattern of nasal epithelia compared with normal epithelia. This test has either very little or no response to chloride free solutions (8).
The role of NGS in diagnosing CF is beneficial for detecting the bacterial pathogens (such as Pseudomonas aeruginosa) during an infection. This can be achieved by resequencing individual colonies and whole populations from single sputum samples from CF patients that is marked by acceleration in the decline of pulmonary function (9). Since CF has a high genetic heterogeneity (due to different types of mutations), it greatly affects the allele detection rate and overall frequency of mutant alleles of genetic tests such as whole genome Illumina sequencing. The algorithm of immunoreactive trypsinogen (IRT) analysis and next generation sequencing (NGS) contributes to an improved timeliness by having a high throughput. NGS also provides visibility into the CFTR gene for molecular diagnostic testing of CF and can be used to make informed family planning decisions and choose optimised treatments, leading to a better quality of life.
However, as Illumina sequencing produces shorter reads, there is still a need for more adequate read lengths of genes to make it an effective test for CF patients (11). Additionally, to limit costs and time, a gene panel of CF mutations would be more beneficial to have a role in mutational searches that can be performed for both CF diagnostics and screening purposes.

Huntington’s Disease diagnostic tests
The clinical diagnosis of HD using a non-NGS technique is based on the neurological evaluation with the manifestation of an obvious extrapyramidal movement disorder, and a positive genetic test for the HD CAG expansion or a confirmed family history of HD (12). The neuropathology indicates loss of medium gamma-amino butyric acid (GABAergic) spiny neurons, sparing of large cholinergic interneurons, and specific neuronal loss of the cerebral cortex (12). The morphometric analyses from MRI scans suggest marked atrophy in the striatum, thinning of the cortical ribbon and evidence of white matter volume loss (12).
A gold standard NGS technique for HD diagnosis is the DNA determination, showing at least 36 CAG-repeats on the huntingtin gene on chromosome 4 (13). This can be tested by using Southern blot for longer repeats that provides accurate size repeat expansions, but the detection rate is low. Completing a WGS is a more useful test for identifying repeat expansions as it is able to identify the genome coverage when detecting the disease compared to WES. The penetrance of HD is unpredicted as some patients may not manifest the phenotype until late in life and will therefore be included in the reference data (14). Thus, having the use of WGS of Illumina will avoid costly unnecessary tests such as MRIs, treatments (i.e. gamma globulin for inherited neuropathy) and additional referrals are strong reasons to increase the appropriate genetic testing used for HD patients (15).
Currently, the main technical limitation of NGS is the inadequate for disorders caused by expansion of oligonucleotide repeats and alterations in highly repetitive DNA regions such as in HD (16). Meaning that additional tests such as Southern blot are required to confirm the diagnosis.
Charcot-Marie-Tooth Disease diagnostic tests
A family history of CMT-like symptoms combined with signs of nerve damage from an individual’s physical exam (leg weakness, deep tendon reflexes), suggest CMT or another hereditary neuropathy (17). If the diagnosis is consistent with CMT, a neurologist will arrange a genetic testing (DNA blood test) to detect the most common genetic defects known to cause CMT and perform a nerve conduction velocity (NCV) that measures the strength and speed of electrical signals transmitted through the peripheral nerves (17). Delayed responses are a sign of demyelination and small responses are signs of axonopathy and is often used to distinguish between CMT types; CMT1 and CMT2 (17). Other non-NGS procedures may include electromyography (EMG) that measures the electrical signs in muscles (17).
Whole genome Illumina sequencing has shown to identify both known and novel genes associated with CMTD that has sometimes been missed using the Sanger sequencing in a diagnostic laboratory caused by small indels of the DNA (17). Thus, a gene panel of all known genes associated with CMT will thereafter be able to link with the patient’s phenotyping shown in the clinic and will increase the throughput, meaning more novel genes will be introduced to the panel (17). Using whole genome Illumina sequencing to detect CMT as a diagnosis has been beneficial to some extent as their degree of exome coverage is of insufficient leading to more genes needing to be covered. For example, having the CTMX, where the X chromosome and many GC rich regions are poorly covered by the WGS, a better option would be to have a disease-targeted sequencing. This will allow the analysis of multiple or more genes known to be related to a given phenotype (16).
The main disadvantage however is the interpretation of all the genes that have been screened, as most of them might not be related to CMT. This makes it more difficult to understand the novel gene and identify the potentially relevant mutation as there are no reliable functional tests to prove the pathogenic nature of a given mutation (17).
Next Generation Sequencing ethical, economical and technical factors
One of the most common reasons for referrals to a specialist clinic is the genetic evaluation of patients that wish to start a family (17). Some of these patients will undergo antenatal testing such as amniocentesis to determine the genotype of the embryo (17). While the requests are a minority, it highlights the importance of ensuring that a mutation is indeed pathogenic in an individual patient, but such a process is becoming increasingly complex with the advent of NGS technologies and the subsequent identification of novel genes (as some could be discovered as very rare) (17). It can also have an impact on the patient’s life (work, future living). These may include HD, where the penetrance is not obvious at the start, but drastically changes with time. This highlights some of the ethical dilemmas that both patients and healthcare professionals may face, considering such tests may determine what future the parents may decide for their child.
Clinicians are often faced with the question whether they should start a diagnostic workup with a disease-targeted test or directly with a genomic analysis (WES or WGS), for the sake of time, cost and efficiency (16). For instance, excellent results have been obtained with WES/WGS for investigation of seemingly genetic disorders that present atypical manifestations that are difficult to confirm using simple clinical or laboratory criteria or otherwise require extensive or costly evaluation. These are usually disorders with high clinical and genetic heterogeneity, such as intellectual disability and congenital malformations (16). The cost of implementation including equipment set up, routine sequencing costs for reagents and consumables as well as post-processing bioinformatics costs is an obvious, but significant factor (18). However, the significant requirements in computation resources and time would render such analyses unusable in a clinical environment (18).
RNA-sequencing and Congenital Muscular Dystrophy
Congenital Muscular Dystrophy (CMD) is a genetic condition that is caused by muscle weakness and wasting starting very early in life. This affects the skeletal muscles that are responsible for the body movements. A patient has completed a whole genome sequencing alongside some of its family members to identify a novel mutation. However, as there was a 10Mb interval identified with the disease but with no obvious single nucleotide observed in the exome region, an RNA-sequencing test can be useful to uncover multiple features of transcriptome and to facilitate the biological applications.
The main applications of RNA-seq analysis are novel gene identification, expression, and splicing analysis (19). This is because it has the ability to reveal unannotated protein- and microRNA-coding genes expressed in the cells without prior knowledge of the reference or sequence of interest (20). It also has the ability to quantify the expression of isoforms and unknown transcripts, and splice analyse exons to identify the functional gene and protein diversification in a disease as CMD (20).
Thus, a combination of long-read RNA sequencing and short-read RNA seq of the patient and the family members will enable characterisation of the splicing landscape of CMD by identifying the allele-specific expressions and disease-associated SNPs (19). In this case, single-cell RNA-seq analysis will be more advantageous as it will provide the expression profile of individual cells. Through gene clustering analyses, rare cell types within the cell population can be identified, thereby applying the study of the cellular heterogeneity and diversity in neuroscience. This will make it easier to identify uncommon RNA but also reveal copy number distribution of the whole mRNA population in individual cells that will be more helpful to understand the causal variant that affects the patient (19). RNA-seq is more sensitive in detecting genes with very low expression and more accurate in detecting expression of extremely abundant genes.
The challenges of RNA require comprehensive solutions including differential gene expression analysis and detection of fusion genes (19). RNA-seq is complicated by having multiple-step processes to identify and quantify all RNA species from the reads sequenced (19). Thus, quality assessment is the first step of the bioinformatics pipeline of RNA-seq and a step before analysis (19). It is also necessary to filter data, removing (trimming) low quality sequences or bases adaptors, contaminations or overrepresented sequences to ensure a coherent final result (19). Another problem in reads mapping is that the polymorphisms are especially common for the large and complex transcriptomes. This leads to sequence reads aligning to multiple locations of the genome resulting in unidentified region of interest that is causing the disease (19).
After getting the read counts, data normalisation is one of the most crucial steps of data processing that is essential to ensure accurate inference of gene expression and subsequent analyses thereof (19). However, there are multiple features of the RNA-seq data that can be taken into account including transcript size, GC content, sequencing depth sequencing error rate and insert size (19). RNA-seq has the benefit of delivering low background signal due to the fact that the DNA sequences are unambiguously mapped to unique regions of the genome and as a result the noise in the experiment is easily eliminated during the analysis (20). These limitations include solving big output files that require high level of volume storage memory, huge obtained data needing required powerful and strong tools and equipment like computation units to process and analyse data (20).
In conclusion, the aim of completing whole genome Illumina sequencing in patients in diagnostic laboratories is to have a higher throughput, more efficient, timely and cost-effective method for genetic diagnosis. This is to detect known and novel genes in an entire human genome for various diseases. Currently, the major limiting factor for genetic testing is the pace of discovery of genes potentially relevant to a phenotype and its interpretations. Furthermore, RNA-seq is another high-throughput, quantitative method allowing us to explore the transcriptome of an organism of interest. This has enabled us to potentially identify a variant call causing a patient in a family.
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Structure and Function of Neurons

The focus of this essay is to give an account of the structure and function of a neuron. A neuron is a solitary specialized cell often found to be part of a neural circuit working within the nervous system. It serves the purpose of propagating signals and provoking responses along the nervous system (Khan Academy, 2018). Neurons differ from most other cells in that most neurons cannot divide after differentiation, as a result once matured if a neuron in the central nervous system has been destroyed it often cannot be replaced (Nicholls et al., 1992.). It is critical to note that the function of the neuron cannot be understood without considering the structure and function of its basic component parts which shall be explored within this essay. In addition, this essay will also look to explore: neuronal classification, neurons ability to transform any kind of signal into an electrical current, and their ability to propagate these signals to provoke a response.
To begin with, we shall explore the structure of a neuron in order to be able to later understand how it can carry out its functions. All neurons obtain a soma, containing the same organelles found in all animal cells. These organelles, however, vary in amount within the soma of a neuron compared to other cells as a reflection of the cell’s specific functions. For instance, the volume of rough endoplasmic reticulum in neurons is richer than glia and other non-neuronal cells. Also present within the soma is cytosol a salty potassium rich fluid within the soma separated from the outside by the neuronal membrane its role shall be briefly be explored farther on. The neuronal membrane encloses the cytoplasm inside and excludes other material within the extracellular fluid bathing the cell. An important feature to this structure is that it is studded with proteins, for example, protein pumps and pores which regulate what substances can enter or exit the cell (Bear, Connors and Paradiso, 2016).
The cytoskeleton is the scaffolding providing the neurons’ characteristic shape, consisting of three types that shall briefly be delved into. Firstly, microtubules are the largest scaffolding unit and run longitudinally down neurites. It is made of polymer strands of tubulin and as a result neuronal shape can be altered by polymerization or depolymerization. Microfilaments are a similar thickness to the cell membrane and found throughout the neuron. They’re made of two thin strands of a polymer formed out of the protein actin braided together and are closely associated to the membrane. Like microtubules they also run longitudinally. They’re believed to aid the changing of cell shape and are involved in the mechanisms of muscle contraction. In addition to usual scaffolding that cells have, neurons in addition have their own more minor scaffolding components known as neurofilaments which provide mechanical strength to the neuron. (Bear, Connors and Paradiso, 2016).
Within nature there is an established relationship between structure and function- nerve cells are one prominent example due to the formation of excessive communication networks. As a result, the usual spherical structure of the cell has become elongated and deformed (Al-Chalabi, Delamont and Turner, 2008). Unique to neurons is the protrusions stemming from the soma required for the receiving and sending of electrical signals making neuronal connection possible. Dendrites are tree-like structures extending from the soma functioning as the antennae of the cell. They are sometimes covered with dendritic spines, that are believed to play a role in isolation of various chemical reactions. These spines are sensitive towards both type and amount of synaptic activity, as an implication, unusual changes to the spines have been shown to impair the function of cognitive capabilities. (Bear, Connors and Paradiso, 2016). For example, Migulel Marin-Padilla and Dominick Purpura (1970) examined the brains of intellectually disabled children using Golgi staining. They discovered low functioning children were found to have fewer dendritic spines and those they did have where misshapen (unusually long and thin). Suggesting intellectual disability reflects on failure of typical structures and circuits forming in the brain (Marin-Padilla and Purpura, 1970 as cited in Bear, Connors and Paradiso, 2016. Pg. 47).
Most nerve cells have one long extension called an axon beginning with a region named the axon hillock. Protein composition throughout the axon is different to that in the soma and neuronal membrane, consequently no protein synthesis takes place here. The axon often forms axon collaterals, these extensions allow the axon to advance considerable distances and carry out its function in communicating with numerous parts of the nervous system. The diameter of the axon is variable ranging from 1µm- 25µm this structural variance is important as it affects the rate of which a nerve impulse can travel. Finally, th axon ends in an axon terminal; the site of synaptic transmission. There are structural differences present here such as: lack of microtubules, synaptic vesicles, inner membrane surface facing synapse densely covered with proteins and its cytoplasm containing many mitochondria. Synaptic transmission of information involves the electrical impulse to be converted into a chemical signal resulting in the release of neurotransmitters stored in the synaptic vesicles. This chemical signal is then converted back to an electrical impulse at the postsynaptic membrane. Modification of this process is involved in functions such as learning and or memory (Bear, Connors and Paradiso, 2016). Sometimes axons are myelinated by either Schwann or oligodendrocytes. This myelination is electrically insulating and has gaps called nodes of Ranvier which allow faster rates of conduction of signals by saltatory insulation (Goetz, 2007).
Neuronal cells can be classified according to both morphology and or functional characteristics. Morphology classification include granule cells these are grain like in shape as they have small cell bodies. Another example is stellate cells these are small interneurons that have a star shaped dendritic tree. They can function as either inhibitory if dendrites are aspinous and excitatory if spinous (Furness, 2018). A contextual example within the mammalian cerebral cortex and hippocampus is the pyramidal neuron. These neurons have a pyramid shaped cell body, with an apical dendrite and several basal dendrites branching extensively to produce a dense dendritic tree. This tree allows many contact points to be created and is covered in spines in close contact to presynaptic terminals of partnering cells (Luo, 2016).
Neurons are also frequently classified by their function. Such as sensory neurons, afferent neurons which carry information about the internal and external world to the central nervous system. They occur in places such as specialized sense organs: eyes, inner ear, skin, nose, tongue, joints. They exhibit specific characteristics in their structure with long dendrites to make many contact points to obtain information from internal or external stimuli and short axons they are pseudo unipolar (Luo, 2016). Examples include visual neurons, cells that respond to light entering the eye and auditory neurons, cells that respond to sound entering the ear. Motor neurons are effect neurons whose function is to carry signals out of the central nervous system to target effector organs such as muscles and glands. Their structure is characterized by short dendrites and long axons allowing them to extend far distances across the body in order to provoke responses. For example, motor neurons found in the spinal cord extend their bushy dendrites within the spinal cord from the spinal cord and project out their axon into muscle. Lastly interneurons can be afferent or efferent and function to convey signals from one neuron to another. They consist of short dendrites and either long or short axons (Psychology Hub, 2018).
Neurons perform their functions in the context of neural circuits; interconnected neurons acting collectively to perform specific functions. An example in vertebrates is those mediating spinal reflexes which can consist of as few as two interconnected neurons. One such reaction is the knee-jerk reaction. Where a sensory neuron detects stretch of muscle spindles caused by impact and convert the mechanical stimuli into an electrical impulse. Two specific functions of neurons are displayed in this example, firstly, is the neurons ability to receive information and secondly, to communicate signals to target cells. The central and peripheral axons of sensory neurons propagate these electrical signals back to the spinal cord in the form of action potentials. In the spinal cord central axons of the sensory neuron establish synaptic connections with dendrites of the motor neurons which terminate at the same extensor. As a result, the action potential from the motor neuron causes the release of neurotransmitters at the motor axon terminal causing contraction. In this case the sensory and motor neurons are excitation however the contraction of a muscle requires coordination as they are antagonistic. Therefore, along with causing the contraction in extensor muscle sensory axons must also inhibit contraction of corresponding flexor muscle. This inhibition is mediated by inhibitory interneurons in the spinal cord (Luo, 2016).
A key function of nerve cells is their ability to convert a signal of almost any kind into an electrical current; most commonly is the transformation of chemical to electrical. All neurons have a resting potential- where the inside of the cell is negative in respect to the extracellular solution. A change in potential therefore propagates an electrical signal which can fall into two dominant classes. The first is called local graded potentials these vary in amplitude depending on the activating stimuli and often only spread short distances from stimulus site. The second category is known as action potentials these are initiated when the localized graded potential is sufficiently large and can depolarize the cell membrane beyond its threshold value (Peterson, 2018). A vital function of neurons is the ability to differentiate the strength of a stimulus and therefore if it is worthy of provoking a response in a very short time period. Action potentials can travel large distances across the body however lack flexibility in amplitude and duration (Nicholls et al., 1992.). It is notably an all-or-nothing event. Action potentials see the rapid membrane depolarization and repolarization; originating in the axon hillock which that contains many sodium and potassium voltage channels. A stimulus causes a change to the nerve cell such as nerve fibres being stretched (Luo, 2016) which then can cause sodium channels to open. As a result, sodium floods into the cell under its diffusion gradient. This results in the final potential of the cell being 30 mV. Sodium channels soon close while potassium channels open causing an undershoot where potential difference hits -85mV. Around this time the sodium-potassium pump regains its function in moving sodium out of the cell and potassium in, in order to preestablish resting potential (Khan Academy, 2018) The action potential propagates down to the axon to the terminal where the electrical impulse is transmitted via an electric or chemical synapse. If it is a chemical synapse a neurotransmitter will be released. (Lodish H, Berk A, Zipursky SL, et al., 2000.). Propagation of the action potential takes place by a process called positive feedback, in which the segment immediately in front of the depolarized section electrically attracts sodium ions. As a result, this immediate section then also gets depolarised (Caurana, 2018)
In conclusion there are obvious structural differences in neurons are compared to other animal cells, such as their ‘deformed’ shape and extensions (axons and dendrites). There are also structural differences in the organelles they contain and their cytoskeleton which was described. It can additionally be noted that neurons carry out an extensive role in the communication of signals allowing us to respond to both external and internal stimuli. Functional neurons where explored and the involvement of neural circuits as well as an example was given to illustrate the vital role neurons play. This function is of huge importance in our ability to survive. Propagation of signals in the form of action potentials was explored as this is a vital function of neurons along with their ability to convert electrical signals to chemical and then back to electric. Therefore, it can be concluded that neurons have three basic functions to receive information, integrate incoming signals and communicate signals to target cells.
Al-Chalabi, A, Delamont, R. and Turner, M. (2008). The Brain. New York: Oneworld Publications p. 29-33
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Bear, M, Connors, B. and Paradiso, M. (2016). Neuroscience. 4th ed. Philadelphia: Wolters Kluwer.
Furness, D. 2018. The different classes of neurons [lecture 2 October 2018]
Goetz, C. (2007). Textbook of Clinical Neurology. 3rd ed. (N.P) Saunders, p.48.
Khan Academy. (2018). Overview of neuron structure and function. [online] Available at: [Accessed 9 Dec. 2018].
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Psychology Hub. (2018). The structure and function of sensory, relay and motor neurons. [online] Available at: [Accessed 12 Dec. 2018]. (2018). The Structure and Function of Neurons – Video