Genetic diagnosis in adulthood. DNA contains all the instructions for the proper functioning of the organism. Therefore, 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 for a more comprehensive study of genetic information.
Advances in sequencing technology: emerging technologies in genetic diagnostics
Next-Generation Sequencing (NGS) is an analytical technology that allows the simultaneous study of millions of DNA sequences from many patients at the same time. The advantages of NGS over traditional methods include: higher throughput and sensitivity in detecting low-frequency variants, faster turnaround time for large sample volumes, and lower cost. The advent of this technology has opened new opportunities for understanding genetic variation, gene expression, and epigenetic modifications.
When ordering genetic diagnostic tests in clinical practice, there are generally two main approaches: sequencing panels of specific genes related to a disease and whole-genome (WGS) sequencing. The latter provides greater flexibility in gene selection or re-analysis in the event of the emergence of new phenotypes. Whole-exome sequencing (WES) is performed by targeted enrichment of exonic (coding) regions, where mutations such as the 85% gene, which cause disease, are typically found. Whole-genome sequencing (WGS) provides more uniform and comprehensive coverage, which is relevant for identifying non-coding variants associated with diseases.
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 component. Genetic testing in adulthood can be particularly helpful. Identifying genetic variants provides highly relevant clinical information that can help determine a patient's prognosis, as well as identify secondary pathologies or complications that may arise. Furthermore, it allows for the establishment of inheritance patterns and helps genetic counselors determine if other family members may be at risk, giving them the opportunity to undergo genetic testing.
Some diseases result from a combination of hereditary and environmental factors or from the interaction of several genes, which complicates diagnosis. Furthermore, not all genes exhibit complete penetrance and may have variable expressivity. Geneticists and genetic counselors consider all of these concepts when evaluating patients' family histories and test results.
So, what does it depend on?
Clearly, genetic diagnosis depends on the advancement of knowledge in this area, since it is possible that the genes related to a disease have not yet been characterized and the genetic architecture of the disease has not yet been established. Genetic diagnosis, and even preventive genetics, are advancing rapidly since the development of next-generation sequencing (NGS) and the creation of biobanks with phenotypic data from patients.
As mentioned, when a patient presents with symptoms consistent with a specific disease, it is possible to conduct a study targeting a well-characterized group of genes associated with that pathology. In these cases, the diagnostic yield is higher, but it is possible that no associated variants will be found in that set of genes. In such cases, if a virtual panel based on exome sequencing is used, it is possible to expand the study to other genes or even perform a diagnostic interpretation.
In the case of these complex phenotypes, which are not consistent with a single genetic disease and where symptoms associated with several body systems overlap, the most appropriate approach is exome or genome sequencing. This is accompanied by diagnostic interpretation. In this type of approach, instead of studying a predetermined group of genes, the patient's signs and symptoms are encoded in HPO (Human Phenotype Ontology) codes, and the genes related to the patient's specific phenotype are identified.
Diagnostic exome and genome throughput.
We have previously mentioned that the 85% variants of disease-causing genes are located in the exome. Therefore, exome sequencing is a highly effective genetic diagnostic tool, although, depending on the pathology, it is increasingly common to request genome sequencing in clinical practice.
The diagnostic yield of exome and genome sequencing varies considerably depending on the pathology being analyzed. While it is generally estimated that the diagnostic yield of exome sequencing can reach 31%, that of genome sequencing can reach, depending on the pathology, 40 or 49%. Reaching a diagnosis by identifying the genetic variant responsible for a complex disease is a significant milestone for the patient. Furthermore, it can improve the patient's treatment and medical follow-up, as well as enable the identification of at-risk relatives and even the development of a family planning strategy when considering having children.
Performing trio genome or exome sequencing, that is, additionally analyzing the parental samples, facilitates the interpretation of the findings in the proband, thus improving the test's performance. Therefore, if available, these samples are often also requested.
Advances in medical treatments for Genetic Diagnosis in Adulthood
By identifying the cause of a genetic disease, it is sometimes possible to implement specific treatments or targeted therapies that reduce or eliminate the impact of the pathology on the patient, although the latter is rare. For example, in diseases like cystic fibrosis, early genetic diagnosis allows for comprehensive patient monitoring to address the complications associated with this disease, and, depending on the mutations, there are even gene therapy-based drugs to improve symptoms. Advances in genome editing techniques have been a key milestone in these types of treatments.
Advances in gene therapy are booming, and treatments are already available for serious diseases such as spinal muscular atrophy (SMN1 gene), which has a single-dose treatment for children under two years old 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 stay abreast of genomic advances to understand all the tools at their disposal. The strategic use of genome and exome sequencing, including in specific panels, not only improves diagnostic performance but also opens doors to secondary findings and opportunities for prevention. The implementation of genetic tools leads us toward more precise, effective, and, most importantly, the best possible patient care.
At Zogen we have tools for accurate genetic diagnosis, contact us And one of our medical specialists will gladly provide you with comprehensive advice.
