Medicina de precisão do Hospital Israelita Albert Einstein

The optimistic future of genetic testing for rare diseases

Read about the importance of exome sequencing for rare diseases diagnosis

Gabriela Colichio

A rare disease is one that affects up to 65 people in every 100,000 individuals. Therefore, rare diseases are a heterogeneous group of diseases that affect a small percentage of the population and are characterized by a wide diversity of symptoms, making diagnosis difficult. The exact number of rare diseases is not known, but studies estimate about 6,000 to 8,000 different types of rare diseases worldwide. Therefore, collectively they represent a significant percentage resulting in a globally relevant health problem.

The number of rare diseases is not accurate and thousands of genes and mechanisms related to rare diseases remain unknown. Over the past 8 years, the exome sequencing in research and in the clinical environment, has proved to be an important tool for the study and discovery of new genes related to rare diseases that were not previously detected in other approaches.

Exome sequencing remains a potential diagnosis for rare diseases. In the study by Wenger et. al. (2017) there is evidence that reanalysis of negative clinical results for genetic variants in exome sequences, in 1 to 3 years, increases the diagnostic result by 10%, because in the initial analyzes there was insufficient evidence of variants or genetic causality.

In addition, in the work of Basel-Salmon et. al. (2019) it was possible to observe that the diagnostic yield is even greater with reanalysis obtained with the cooperation of the responsible physician, with estimates of up to 12%. In other articles, they show that the cooperation with research laboratories can provide additional increases, driving the application of new computational tools and sequencing of family members.

The technical limitations of exome sequencing are well known, and in the last decade, it has been possible to increase the coverage of genome sequencing by providing information on variants in promoters and non-coding regions. In addition, computational tools continue to improve and facilitate the identification of these variants.

The interpretation of variants in non-coding regions is complex due to the lack of information about how non-coding DNA regulates gene expression. The lack of appropriate control databases and computational tools to predict impact variants, and the fact that each of these non-coding variants probably affects a single patient or family, makes it difficult to establish pathogenicity.

Therefore, there is a great opportunity in public health accuracy to understand the cause of each rare disease and to provide an accurate diagnosis for each patient. The sequencing remains important and is becoming an important molecular diagnosis, with a notable impact on public health. Many emerging technologies appear to play an essential role in diagnosis and for patients who remain undiagnosed, the future looks bright.


[1] BASEL-SALMON, Lina et al. Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested. Genetics in Medicine, v. 21, n. 6, p. 1443-1451, 2019.

[2] BOYCOTT, Kym M. et al. A diagnosis for all rare genetic diseases: The horizon and the next frontiers. Cell, v. 177, n. 1, p. 32-37, 2019.

[3] BOYCOTT, Kym M. et al. International cooperation to enable the diagnosis of all rare genetic diseases. The American Journal of Human Genetics, v. 100, n. 5, p. 695-705, 2017.

[4] ELDOMERY, Mohammad K. et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome medicine, v. 9, n. 1, p. 1-15, 2017.

WENGER, Aaron M. et al. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genetics in Medicine, v. 19, n. 2, p. 209-214, 2017.

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