Genetic diagnosis in adulthood

DNA contains all the instructions for the correct functioning of the organism, so it is logical to think that genetics plays a fundamental role in people’s health. As knowledge in genetics has advanced, the underlying causes and mechanisms of many diseases have been identified and, in some cases, this has made it possible to establish treatments and strategies to reduce the impact of the disease on the patient. The use of genetic diagnosis has been boosted by technologies such as exome and genome sequencing, which allow a more complete study of genetic information.

Advances in Sequencing Technology: Emerging Technologies in Genetic Diagnostics

Next Generation Sequencing (NGS) is an analysis technology that allows the simultaneous study of millions of DNA sequences in many patients at the same time. The advantages of NGS technology over traditional methods include: higher throughput and sensitivity in detecting low frequency variants, faster turnaround time for large sample volumes, and lower cost. The arrival of this technology has opened up new opportunities for understanding genetic variation, gene expression and epigenetic modifications.

When requesting genetic diagnostic tests in clinical practice, there are mainly and generally two approaches; the sequencing of specific gene panels related to a specific disease and the sequencing of the exome or whole genome, which provides greater flexibility in the selection of genes or reanalysis in case of the appearance of new phenotypes. Whole Exome Sequencing (WES) is performed by targeted enrichment of exonic (coding) regions, where 85% of disease-causing mutations are usually found. Whole genome sequencing (WGS) provides a more uniform and broader coverage, which is relevant for the identification of non-coding variants related to disease.

Genetic Diagnosis in Clinical Practice

In the clinical setting, genetic diagnosis plays a crucial role in identifying the cause of diseases suspected of having a hereditary character. The identification of genetic variants provides information of great clinical relevance, which can help to determine the patient’s prognosis, as well as the identification of secondary pathologies or complications that may arise. Additionally, it allows establishing a pattern of inheritance and helps the genetic counselor to establish whether there may be other family members at risk, giving them the opportunity to perform a genetic study.

Some diseases are the result of a combination of hereditary and environmental factors or the interaction of several genes, which complicates the diagnosis of the pathology. Additionally, not all genes show complete penetrance and may have variable expressivity. All these concepts are handled by geneticists and genetic counselors when evaluating the family history of patients, as well as the results of the studies.

Obviously, genetic diagnosis depends on the advancement of knowledge in this area, as it may happen that the genes related to a pathology are not yet characterized and the genetic architecture of the pathology is not yet established. Genetic diagnosis and even preventive genetics are advancing at great speed since the development of NGS and the creation of biobanks with phenotypic data from patients.

As mentioned, in cases in which the patient presents symptoms compatible with a specific disease, it is possible to perform a targeted study of a well-characterized group of genes associated with that pathology. In these cases the diagnostic yield is higher, but it may happen that no associated variants are found in that set of genes. In these cases, if it is an exome-based virtual panel, it is possible to extend the study to other genes or even perform a diagnostic interpretation.

In the case of these complex phenotypes, not compatible with a single genetic disease where symptoms associated with various body systems overlap, the most appropriate approach is exome or genome sequencing accompanied by a diagnostic interpretation. In this type of approach, instead of studying a group of predetermined genes, the patient’s signs and symptoms are encoded in HPO (Human Phenotype Ontology) codes and a search is made for those genes related to the patient’s specific phenotype.

Exome and diagnostic genome yield

We have mentioned above that 85% of the disease-causing variants are found in the exome, so the diagnostic exome is a very effective genetic diagnostic tool, although depending on the pathology it is becoming more and more frequent to request the diagnostic genome in clinical practice.

The diagnostic yield of the study of the exome and genome is quite variable depending on the condition analyzed, although it is generally estimated that the diagnostic yield of the exome can reach 31% while that of the genome can reach, depending on the pathology, 40 or 49%. Reaching a diagnosis by establishing the genetic variant responsible for a complex disease is an important milestone for the patient. In addition, it can improve the treatment and medical follow-up of the patient, as well as making it possible to search for relatives at risk and even to establish a family planning strategy when it comes to having children.

The performance of the diagnostic genome or exome in trio, i.e. by additionally analyzing the progenitor samples, facilitates the interpretation of the findings found in the proband, thus improving the performance of the test. For this reason, on many occasions, if available, they are also requested.

Advances in medical treatments

By establishing the cause of the genetic disease, in some cases it is possible to implement specific treatments or targeted therapy that reduces or eliminates the impact of the pathology on the patient, although the latter is rare. For example, in diseases such as cystic fibrosis, an early genetic diagnosis allows exhaustive follow-up of the patient to address the complications associated with this disease, and even, depending on the mutations, there are drugs based on gene therapy to improve symptoms. Advances in genomic editing techniques have been a key milestone in this type of treatment.

Advances in gene therapy are booming and treatments are now available for such serious diseases as spinal muscular atrophy (SMN1 gene), which has a single-dose treatment for children under two years of age approved by the national health system in Spain, or retinitis pigmentosa caused by mutations in the RPGR gene.

For healthcare professionals, it is important to keep abreast of genomic advances to be aware of all the tools available to them. Strategic use of the genome and exome, including in targeted panels, not only improves diagnostic yield, but also opens doors to secondary findings and opportunities for prevention. The implementation of genetic tools leads us towards more accurate, effective and, most importantly, the best possible patient care.

At Veritas we have tools for accurate genetic diagnosis, contact us and find out how you can collaborate.