Next Generation Sequencing, Learning Disabilities and Development Defects
Abstract
The development and adoption of next generation sequencing (NGS) technology in genomics is undoubtedly one of the greatest inventions of science towards creating a healthy global environment. NGS is fast transforming and revolutionizing the entire clinical practice and approach to heterogeneous and rare disorders that include learning disabilities and birth defects that continue to affect millions of people including children across the world. This paper seeks to explore the tenets and approaches of next generation sequencing that have since been welcomed into the world of medical genetics. It defines and briefly outlines the different approaches of NGS towards gene sequencing. With the focus on different learning and developmental disorders, it explores the benefits of next generation sequencing approaches to both the affected children and their families. Bearing in mind that most of these conditions have for many years been misdiagnosed, this paper goes ahead to examine the main problems that impede obtaining a diagnosis in children with these conditions. Through critical examination of relevant literature, it endeavors to explore the various large scale genomic projects that are funded for research to look into the genomic basis of both inherited and acquired developmental disorders and learning disabilities among other conditions. Many nations in the world including Britain, the United States and Canada have invested heavily in human genomic projects and thus, the achievements of the projects featured in this paper in the last five years are evaluated with a special focus on UK’s 100,000 Genomics Project of 2012.
Introduction
In a 2011 study that was conducted in the England, an estimated 1,198,000 people in the country had learning disabilities which roughly represent 2% of the entire population.1 Furthermore, there was a total of 0.8 million children with disabilities representing 6% of all children. Strikingly, children having neurodevelopment disorders and related developmental conditions formed the largest proportion with the prevalence being estimated at 3.5 % of all children in the United Kingdom.1, 2
Development and learning disabilities refers to a range of conditions that result from an impairment in either the physical, learning, verbal communication or behaviors. some of these conditions are inheritable in the sensed that they can be transferred from the parent to offspring while others are de novo in that they arise independently without having necessarily been have inherited.1, 3 Examples of these specific learning disabilities and development deficits in children include Attention Deficit Hyperactivity Disorder (ADHD), Auditory processing Disorder (ADP), Dyscalculia, Dysgraphia, Dyslexia, Language processing Disorder, visual perceptual deficit, including birth defects such as cleft lip and cleft palate, polydactyly (extra digits), phocomelia (defect in the limbs), heart defects which include the Tetralogy of fallot among other defects and disorders.1, 2
Next Generation Sequencing
The Next Generation Sequencing (NGS) refers to a number of different up to date DNA sequencing technologies that allows researchers to sequence nucleic acids faster and cheaper as compared to the traditional Sanger sequencing that is still widely used across many parts of the globe today. The next generation sequencing is a term that is used to describe a DNA sequencing technique that has changed the face of research in genomics forever.4 The Next generation sequencing abbreviated as NGS has a enabled scientists to effectively sequence the entire human genome within the shortest possible unlike the Sanger sequencing technology which would take over a decade to deliver results about human genome. The different platforms of Next Generation Sequencing that include Illumina (Solexa), Roche 454, Ion Torrent: Proton/PGM and SOLiD sequencing perform the crucial task of sequencing thousands and millions of significantly small DNA fragments in parallel.4, 5 Later, Bioinformatics analysis is then employed to piece together the various fragments of DNA sequenced through mapping the readings to the individual orientation genome of interest. According to Behjati and Tarpey, the multiple sequencing of beach of the 3 billion bases found in the genome of human beings ensures accuracy in the data that obtained thus an insight into unanticipated DNA dissimilarity and variation.4, 5
The Benefits of Next Generation Sequencing (NGS) Approaches
Non-syndromic cleft lip and cleft palate is a condition that continues to affect so many children in the United Kingdom with its frequency of occurrence being relatively high.6 However, only a substantial proportion of genetic defects and causal factors have been singled out with the help of Sanger sequencing approaches and genome-wide association studies whose focus has been on the common genetic variations ignoring the much a rarer and uncommon genetic variants. NGS carries a promise of hope in the sense that its ability to sequence millions of human genes will ensure that such rarer variants are taken into consideration.6 This will benefit affected children and patients at large because it will open up new insights into the biological mechanisms that characterize the condition. The success and adoption of NGS will hence lead to remarkable improvement in treatment for cleft palate and lip cheaply since the sequencing that is based on analysis will automatically become invaluable. Next Generation Sequencing approaches will ease the burden on families of children with Cleft palate and cleft lip in the sense that it will lead to an enhancement in forecast and prevention of the condition before it finally becomes problematic.
Even though NGS lacks the capacity to offer explanation to the majority variance in most development and learning disabilities such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorders (ADHD), it carries a promise for an immeasurably better understanding of their causes which will in turn lead to better diagnostic and therapeutic.7 NGS approach will automatically improve the diagnosis of ADHD and ASD which will then lead to improved management of these disorders. Lionel et al through their experiments found out that neuronal deletions of ASTN2 and ASTN2 intronic gene designated TRIM32 had a strong association with the two conditions.7, 8 However, in order to ascertain the true extent of their finding after examining 248 ADHD and 349 ASD patients, the researchers had to screen 89,985 subjects with 64,114 of them having neurodevelopmental defects that the true extent of their finding was ascertained.8 This exercise was not only expensive but also time consuming and tedious. NGS will ensure that such diagnostic procedures are fastened in order to enable effective management of the patients and also save the resources and time of their families.
One of the genes that cause polydactyly; a condition where a person has excess digits either on their hands or feet is GL13 which in itself is transcriptional repressor.9 It is important in the patterning of body tissues and organs in fetal development and its mutation is associated with two types of polydactyl; isolated post-axial polydactyly and pre-axial polydactyly. Studies have associated this birth defect to Joubert Syndrome (JBS); a neurodevelopmental disorders belonging to ciliopathies which is a group of genetic disorders characterized by dysfunctional primary cilia.9 Polydactyly is usually an extra-neurological symptom of JBS. More than 20 genes have been associated with JBS making its molecular diagnosis utterly challenging. NGS will improve immensely the diagnosis of Joubert syndrome according to Kroes et al.9 NGS technology is of great importance in heterozygous diseases where targeted approach is employed. This means that patients affected by this genetic developmental disorder can easily be diagnosed a plan of management drawn. Furthermore, the families of affected patients have an opportunity to save on their resources since it is faster and cheaper.
It is estimated that close to 70,000 people in Britain suffer from various muscular disorders and specifically dystonia majority of who are children.10, 11 Muscular dystrophy is an example of inherited diseases that impede the normal functioning of voluntary muscles and is characterized by progressive weakening of the affected children.10 The commonest example include Duchene, Becker, Limb-girdle, congenital Fukuyama muscle dystrophy known for causing brain abnormalities and seizures and congenital muscular dystrophy with deficiency of myosin. These developmental disorders show huge phenotypic variations, the associated genes are significantly large in size and their genotype-phenotype correlation is poor making the use of conventional and traditional gene sequencing approaches less effective.10 The next generation sequencing approaches are particularly useful in the diagnosis of these muscular disorders in children owing to its powerful ability to pick out genetic variations at a base pair level.11 The first steps towards applying NGS in the diagnosis of muscular disorders have succeeded in describing point mutations in DMD and TTN genes associated with various a wide array these disorders including Cardiomyopathies.11 NGS is will benefit thousands of patients in the united kingdom in the sense that diagnosis of muscular disorders at gene level which has been difficult for many years will be possible making treatment and management possible too. The use of NGS will amplify the number of genetically established patients by at least 10 – 15%.
Problems that impede obtaining diagnoses for learning and developmental disorders
Autism is a childhood mental problem that makes communication and relationship establishment difficult, Auditory processing Disorder (ADP), Dysgraphia, Language processing Disorder, visual perceptual deficit and intellectual disabilities are often very hard to diagnose and most of the times they are mistaken for each other.12 Their diagnoses is problematic owing to the reality that a problem in cognition, verbal communication or even behavior has a huge tendency to have secondary effects on all the other areas making the work of separating effect from case very difficult. Usually, most developmental conditions of cognition and intellectual abilities in childhood whether inherited or de novo have complex interactions of symptoms that more often than not overlap.12 Improper diagnosis of such developmental disorders greatly hinders the process of providing an appropriately targeted therapy and management of specific conditions.
According to the National Joint Committee on Learning Disabilities, the biggest impediment to obtaining diagnoses and management of most learning disabilities and developmental disorders in children is inapt diagnostic practices and modes of operations that contribute largely to misclassification and wrong diagnosis of these conditions.13 First, diagnosing learning disabilities ion children is difficult because of lack of observance to one and consistent way of defining learning disabilities with emphasis on inherent and lifelong nature of the conditions.13 Perspectives and opinions vary between medical practitioners and on what constitutes learning disabilities. Approaches to classifying learning disabilities differ greatly between people and this according to NJCLD is a major contributor to erroneous inclusion of individuals whose conditions and problems may not be associated with learning disabilities and the exclusion of those whose deficits are true manifestations of learning disabilities.13
Most developmental disorders that involve genetic mutations that are either inherited or acquired, obtaining diagnosis is difficult because very many mutations can take place within a given gene and result in a particular disease.2, 5, 13 For instance so many mutations can occur in the DMD gene and also in the TTN gene and still result in muscular dystrophies in the child. It is tasking, expensive and time consuming to sequence the entire gene such as the DMD gene in order to ascertain the exact type of mutation that led to the disorder because the gene is large.11 DNA testing as one of the ways to make diagnosis is limited by such factors making the process of obtaining a diagnosis quite hard. Nonetheless, the introduction of NGS promises faster, cheaper and efficacious sequencing of such human genes in order to improve diagnostics of developmental disorders.4
The apparent shortage of competent personnel and relevant programs designed to diagnose, support, accommodate and guide teachers on how to meet the needs of children who show the sings of having learning disabilities is another problem to diagnosis of learning disabilities.1, 2 The belief that underperformance in class is similar or synonymous to a disability in learning continues to pull back efforts and programs put in place to enhance diagnosis and management of learning disabilities. Understanding learning disabilities is important not only to medical practitioners but also teachers who keep abreast with children’s learning process in schools.1 Having competent personnel to aid in diagnosing learning disabilities will go a long way in correcting the assumption that diagnosis of learning disabilities can only be done through quantitative means.
Large Scale Genomic Projects Funded For Research Into The Genomic Basis Of Learning Disabilities And Development Disorders.
In December 2012, the government of UK under the leadership of its prime minister adopted a program that aims at sequencing 100,000 human genes as part of its Life’s sciences strategies. The 100,000 Genomes Project was part of the 467 million dollars initiative by the UK’s government National Health Service.14 The main aim of the project is to sequence more than 100,000 human genes from patients with rare disease conditions, inherited and acquired developmental disorders in both children and adults, malignant conditions and other infectious diseases by the end of 2017. The desire to develop and discover new possibilities in the power of genetic medicine drove the establishment of 100,000 Genomes Project whose successes have been immense and its contribution to clinical practice significant.14 Through the linkage of scientific insights to specific developmental disorders and learning disabilities, this project seeks to obtain much better diagnoses, establish tailored treatments for specific patients with specific conditions and ultimately scale new heights in the industry of genomics in the modern world.
By the end of 2015, the project had already registered notable successes in its operations with a total enrollment of 3500 people with very rare developmental disorders and 2000 cancer patients. The projection by then was that the number of people with rare diseases will constitute up 50,000 of the ultimate figure, and since most if not all rare diseases are inherited, the genome of the affected patients will have to be sequenced alongside two or more genomes of their close relatives.14 In 2016, the first lot of children who were enrolled in the project received their results at Great Ormond Street Hospital (GOSH). The patients are reported to have had rare undiagnosed genetic disorders and the whole genome sequencing succeeded in pointing out the underlying genetic mutations that were responsible for their conditions.
The Human Genome Project (HGP) refers to an American based project that was funded by the National Human Genome Research Institute (NHGRI) whose main aim was to sequence 3 billion DNA letters that constitute the human being genetic book.15 The project was fruitfully completed back in 2003 April and since then, the NHGRI has conducted and funded numerous research projects to investigate the role of genome in health and disease. The exploration of the role of genes in the development of developmental disorders and learning disabilities has formed one of the objectives of NHGRI sponsored projects in an effort to improve their diagnoses and treatment as well. In 2011, NHGRI launched the center for common disease genomics which has since utilized genome sequencing to examine the role of genomics in diseases and developmental disorders autism being given a special focus.15 Huge steps have since been realized in terms of diagnosis and tailored treatment towards these conditions. Also, a NHGRI funded research in 2016 identified a genetic basis for a rare but serious condition in children due to vibration called vibratory urticarial.15
In March 2016, the Canadian government through Genome Canada and the Canadian Institutes of Health Research invested 149.8 million dollars in the Large Scale Applied Research Project (LSARP).16 Up to seventeen projects were sponsored and their focus was on the application of gene sequencing to make diagnosis and modify treatments for patients with epilespsy, autism, metastatic diseases, cardiovascular and atypical neurological illnesses, HIV/AIDS among others. One of the projects named “Enhanced CARE for RARE genetic diseases in Canada” sought to explore the role of genetics in some developmental disorders that affect children such as Muscular dystrophy. Dr. Kym Boycott and his team have since recorded immense progress in identifying some of the genes responsible for many such conditions in many Canadians who were undiagnosed with rare disorders.16
Conclusion
Next Generation Sequencing approaches towards the diagnosis and management of learning and developmental disorders in children in the United Kingdom is set to change completely the field of diagnostics. NGS carries the promise of enhanced health care not only for conditions with genetic basis but also in terms of drug development and administration with both medical practitioners and patients standing to benefit immensely. Most developmental disorders and learning disabilities are difficult to diagnose which complicates their treatment and management. However, with NGS the task is made easier and the outcomes more favorable. The field of genomics and its role in disease and health will only grow if more and more projects are supported, funded and their recommendations taken into consideration.
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