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In the last four decades, through advances in immunology and genetics, more than 400 different genes have been discovered that affect the immune system in terms of its development, function or both, related to the development of “Inborn Errors of Immunity – IEI” [1,2]. In most cases, monogenic immune defects are the cause of IEIs, but they can also have a more complex polygenic origin. Individually, each of these diseases affects few people, but collectively they represent a large number of different diseases that affect a significant percentage of the population.
Diagnosis of innate immunity errors and their relevance
Phenotypic and functional characterization are the current diagnostic methods for IEIs, and are quite time-consuming [3,4]. It is important to note that many patients with similar genetic deficiencies present huge clinical and laboratory diversity [5]. The opposite is also true, as mutations in different genes can lead to similar phenotypes [6]. This diagnostic difficulty leads to delay in starting an appropriate treatment, increasing morbidity and mortality [7].
In addition, the correct identification of genetic defects is important for genetic counseling, as in cases of family planning and prenatal examinations of families with patients affected by EIIs [8]. These advances have led to the development of diagnostic and therapeutic tools and potential genetic therapies (Immunodeficiency resources – IDR); in addition, the availability of specific therapies for disorders in a given metabolic pathway is gaining importance, allowing for much more effective treatments, greatly reducing the morbidity and mortality of these diseases.
Development of disease-associated genetics in humans
Many genes associated with Mendelian disorders have been discovered through linkage mapping or sequencing of candidate genes. However, a substantial knowledge gap about the genes that cause many of the rare Mendelian phenotypes still exists [10]. The advent of massive parallel sequencing technologies that simultaneously amplify and sequence millions of fragments (known as Next-Generation Sequencing, NGS) has revolutionized the field of human genetics, allowing sequencing of the complete human genome in just a few days and substantially reducing the cost of sequencing of large genomic regions compared to the Sanger method [11].
NGS methods and IEI diagnosis
NGS is a set of fast, accurate technologies, with relatively low cost and high performance that have identified mutations in new genes associated with diseases, including genes associated with IEIs [12,13,14,15,16,17]. Although these technologies offer complete sequencing data, it is extremely challenging to distinguish pathogenic variants from the 3.2 billion base pairs present in the human genome [18]. Some approaches can facilitate the evaluation of the genes of interest, such as limiting sequencing to only the coding region of the genome, that is, the exome [19]. Although the exome represents only 1% of the genome, it harbors approximately 85% of the harmful mutations. The growing number of exome sequencing studies demonstrates the power of this approach in mapping genes involved in Mendelian diseases, as well as suggesting its application in complex diseases [20].
How to assess the tsunami of data obtained in the NGS?
Whole exome sequencing studies (WES) identify approximately 20,000 to 35,000 single nucleotide variants (SNVs) per exome, depending on the technology used and the ethnic origin of the patients [21]. The identification of gene variants associated with diseases allows the improvement of the diagnosis and the initiation of biological investigations. The real importance of these studies is the demonstration that this approach is useful to characterize the genetic bases of rare monogenic diseases using a small number of affected individuals [22,23,24].
The combination of whole exome sequencing with an efficient variant filtering technique represents an effective strategy for the identification of genes associated with Mendelian diseases, as we can assess by the growth in the number of genes related to innate immunity errors in the last decade. In the 2009 classification, 174 IEI-causing genes were known; 205 genes in 2011; 235 in 2013; 269 in 2015; 354 in 2017 and 430 in 2019, that is, more than 250 new genes have been described in a decade, with the fundamental help of NGS.
Are IEI rare diseases? What is the consequence of this?
The prevalence of symptomatic IEIs varies from 1: 10,000 to 1: 100,000 live births, but higher frequencies can be seen in populations with a high degree of inbreeding or among genetically isolated populations [25]. Affected individuals have difficulty in obtaining diagnosis and referral due to the lack of knowledge of health professionals in general about the identification and tracking of these cases. Although rare, these diseases are chronic and severe and early diagnosis could mean a great improvement in the quality of life of patients affected by IEIs. Recently, the improvement of the knowledge of the pathophysiology of IEIs at the molecular level led to the development of targeted therapeutic interventions.
Some drugs were developed specifically for these diseases, but also drugs developed for other diseases were redirected to modulate the function of intracellular pathways whose function is increased or decreased as a result from specific genetic defects. Even defects in the same gene could need different treatments, depending on if the mutation leads to gain of function or loss of function of the respective proteins encoded by this particular gene [26]. This approach allows targeting a specific function of a cell, instead of affecting the whole immunity, avoiding adverse effects on other tissues and systems of the body. It is true that precision medicine is showing its great potential nowadays in several areas of medicine, but in the forecoming years, it will change the way we treat diseases as a whole.
About the author: Dr. Dewton de Moraes Vasconcelos has a degree in Medicine, a master’s degree in Allergy and Immunopathology from the Faculty of Medicine of the University of São Paulo (FMUSP), a doctor in Immunology from the Institute of Biomedical Sciences at USP, and is currently the physician responsible for the Dermatological Outpatient Clinic. of Primary Immunodeficiencies of HC-FMUSP, and researcher associated with LIM-56.
