Genetic tools for the diagnosis of rare diseases

Rare diseases present a unique challenge due to their low prevalence and the complexity of their diagnosis. To improve the quality of life of patients with rare diseases and facilitate the development of targeted therapies, early diagnosis is key. For this reason, genetic tools have become an essential resource for the diagnosis of these pathologies, allowing a more personalized and precise approach to patient care. On the occasion of World Rare Disease Day to be held on February 29, we want to give visibility to the importance of genetic diagnosis to improve the quality of life of patients with rare diseases and facilitate the development of targeted therapies.

What do we understand as rare diseases?

Rare diseases are a group of medical disorders that affect a minority of people compared to common diseases. They are characterized by their diversity in symptoms and signs, which can vary significantly from one disease to another and even among patients sharing the same condition.

It is estimated that 72% of these diseases have a genetic origin, while others are due to infections, allergies and environmental factors. Although rare, these diseases share common characteristics, as they are usually severe, debilitating, chronic, degenerative and often life-threatening conditions. In addition, they often have an early onset, can impact an individual’s independence and generate a variety of chronic pain.

The definition of rare diseases differs in different regions of the world, based on their demographic characteristics and health systems. In Europe, a disease is considered rare when it affects less than 1 person in every 2,000 individuals, while in the United States, the criterion for identifying and classifying rare diseases is that the number of affected individuals should not exceed 200,000.

It should be noted that, although each rare disease individually may be rare, together these diseases affect a significant number of people worldwide. It is estimated that between 4% and 6% of the world’s population lives with a rare disease, which equates to approximately up to 450 million people affected globally. This figure represents a significant number and has a considerable impact on the healthcare system and medical research in general.

Main problems faced by those living with rare diseases

Lack of knowledge, difficulty in accessing relevant information and the scarcity of research and specialized centers for rare diseases make living with them complicated for both patients and their families.

One of the biggest challenges for these patients is to achieve an accurate and specific diagnosis of the disease. Sometimes relatively common symptoms can mask underlying rare diseases, which can lead to misdiagnosis and delayed initiation of treatment. It is estimated that in approximately 30% of cases, an early and accurate diagnosis could have prevented a worsening of the disease. Therefore, it is of utmost importance to detect the specific pathology and start appropriate treatment to address the patient’s needs, in order to delay or even avoid complications in symptomatology and avoid unnecessary interventions.

In addition, living with a rare disease can have both an emotional and financial impact. Uncertainty, anxiety, depression and stress are common due to lack of information, difficult access to resources and the social stigma generated around these diseases, among many other obstacles.

Diagnostic tools

The diagnosis of rare diseases is a great challenge since the patient’s clinical picture cannot always be related to a specific disease, making it difficult to find an appropriate treatment.

Even so, diagnostic tools for rare diseases have made significant progress thanks to advances in genomics and next-generation sequencing technology. These tools are key to being able to adapt the medical management of the patient and to address symptomatological treatment early. In addition, if performed on newborns who present signs and symptoms of rare diseases, they make it possible to determine the origin of the pathology and help those couples who want to have more children.

The main techniques include:

• Gene panels: Gene panels are tools that simultaneously analyze a specific group of genes known to be associated with a disease or group of diseases.
• Whole exome sequencing (WES): This technique focuses on sequencing all the exons, i.e. the protein-coding regions of the genome. WES can help identify disease-causing mutations in known genes.
• Whole genome sequencing (WGS): WGS involves the complete sequencing of an individual’s entire genome. This technique is more comprehensive than WES and can detect changes in non-coding regions of the genome, which is useful for identifying mutations in regulatory regions or other genetic changes.

Exome and Diagnostic Genome

For rare diseases and complex clinical cases, exome sequencing and whole genome diagnostic sequencing represent the most comprehensive tools available. In these cases it is essential to perform a clinical interpretation of the genetic variants according to the symptomatology presented by the individual and thus reach the patient’s diagnosis.

Exome or Genome Diagnostics are especially useful in cases in which the patient presents a complex clinical picture that does not correspond to any specific pathology and affects different organ systems of the individual. For this it is essential to have the patient’s entire clinical history, which enables the specialist to objectively define the patient’s HPOs and with them the genes to be studied. HPO stands for Human Phenotype Ontology, and is used internationally to establish phenotypic abnormalities in human diseases.

It is estimated that in 85% of cases, disease-causing variants are found in coding regions, so the diagnostic exome would be a valid approximation in most cases. However, the diagnostic yield of the genome is slightly higher than with the diagnostic exome, and can reach a yield of 40% depending on the pathology studied, because the genome analyzes non-coding regions.

Exome and genome-based diagnostics in TRIO

Following this line, both the exome and the diagnostic genome can benefit from the option of sequencing parental DNA, known as TRIO diagnostics.

This option facilitates the identification of variants possibly related to the disease and helps determine whether they are inherited or de novo from family segregation studies. Together with the patient’s clinical information, this tool allows a more effective and accurate analysis of the possible causes of the disease, resulting in a significant improvement in the diagnostic process.

Diagnostic panels

In cases in which the clinical picture presented by the patient is characteristic of a disease or group of diseases, it is possible to direct the study to the set of associated genes. Such tests are called diagnostic panels, and consist of whole exome sequencing, but with a focused analysis of the genes of interest. Some laboratories opt directly for the sequencing of the required genes, which is a disadvantage, since with whole exome sequencing a reanalysis of the genomic data can be performed in case no variant of interest is detected in the genes analyzed.

Diagnostic panels are usually focused on certain areas, such as neuromuscular disorders, cardiovascular disorders or metabolic diseases, among others. Veritas offers a broad portfolio of diagnostic panels, as well as the possibility for the prescribing physician to design his or her own gene panel according to the patient’s needs.

Considerations in the use of diagnostic genetic services

When sequencing techniques are used for diagnosis, the technology used for variant detection is important, but there are other aspects to take into account.

In cases where the patient presents a rare disease with a complex clinical picture, a good interpretation of the variants found by experts in the field is crucial to reach an accurate diagnosis. In addition, the quality and coverage of the genetic analysis performed must be taken into account, as insufficient sequencing can affect the accuracy of the diagnosis.

Therefore, it is of vital importance to choose a diagnostic service that includes high quality sequencing and an expert team in genetic counseling and interpretation key to the diagnosis of rare diseases.

At Veritas, we believe in the importance of giving visibility to rare diseases in order to achieve advances in diagnosis and improve the lives of patients and their families. That is why we offer sequencing services with diagnostic interpretation. The GenomeDx option is offered by Veritas in collaboration with the Children’s Hospital of Philadelphia, a leading hospital considered one of the top 50 hospitals in the United States and a leader in specialized genomic interpretation. In addition, we offer a comprehensive set of specific or customizable diagnostic panels for those cases where a targeted evaluation is required. Our goal is to provide quality medical care and a more hopeful outlook for the management of rare diseases.