Home Medizin Exomsequenzierung entschlüsselt komplexe genetische Diagnosen bei Wachstumsstörungen

Exomsequenzierung entschlüsselt komplexe genetische Diagnosen bei Wachstumsstörungen

von NFI Redaktion

Researchers in Brazil recently published an article in the Journal of Pediatrics describing the case of a nine-year-old boy who was admitted to the hospital with several overlapping conditions that made diagnosis challenging. The boy presented with symptoms such as short stature, thin tooth enamel (dental enamel hypoplasia), moderate intellectual disability and speech delay, asthma, slightly altered blood glucose levels, and a history of recurrent infant infections.

Using exome sequencing, which specifically analyzes the protein-coding portion of the genome, the team searched for genetic mutations and found them in the GCK and BCL11B genes. The resulting diagnosis was monogenic diabetes and T-cell anomaly syndrome, both rare conditions. Identifying the exact cause of the problem and discovering a blood sugar alteration had a significant impact on treatment decisions.

This is one of six cases of syndromic growth disorders with multiple genetic diagnoses (two or more different genetic diseases in the same patient) described in the article. It is a study conducted by researchers from the University of São Paulo’s School of Medicine (FM-USP) with support from FAPESP.

„Exome sequencing is a very useful technology to shorten the so-called diagnostic odyssey – the long journey that patients with rare or complex diseases have to endure before receiving a proper diagnosis. Ten years ago, private labs charged 10,000 BRL. The price has since dropped to 4,000 BRL [about USD 800]. This is still a significant amount of money for a test, but it has proven crucial for an accurate diagnosis and treatment in such cases,“

said Alexander Augusto de Lima Jorge, the last author of the article.

The team sequenced the exome of 115 patients with syndromic growth disorders of unknown cause, diagnosing 63 based on genetic analysis; 9.5% of them had a multiple diagnosis, much more than in previous studies.

„The cases involved two or more rare monogenic diseases in the same patient. Such cases are very difficult to diagnose, particularly through clinical assessment alone. The study underscores the need to implement comprehensive genetic tests, such as whole exome or whole genome sequencing, in these patients,“ said Lima Jorge.

„There are numerous rare diseases, including growth disorders, so it is naturally difficult to identify many of them. It is estimated that between 5 and 10% of the world’s population suffer from a rare disease.“

According to Lima Jorge, short or tall stature is not a diagnosis, but a clinical finding. „Short stature may have an external cause, such as an infection or malnutrition. Nevertheless, genetic factors will always be important for growth. In healthy children with short or tall stature as the only manifestation, there is probably a polygenic basis, but in syndromic growth disorders, where short or tall stature is accompanied by other findings such as intellectual disability, deafness, autism spectrum disorder, or malformation, a change in one or more genes is more likely to justify the complex phenotype involved,“ said Lima Jorge.

Given the results, the researchers advocate for the recognition of multiple genetic diagnoses as a possibility in complex cases of growth disorders and open new perspectives for the treatment and genetic counseling of these patients, instead of the typical paradigm that requires a single diagnosis to account for all findings.

In the article, the researchers state that the development of next-generation sequencing techniques, such as whole exome or whole genome sequencing, has made the selection of a single gene as a candidate to explain a case unnecessary. This particular advantage has proven useful in the research setting to promote the discovery of new disease-associated genes, advance the study of diseases with a high degree of genetic heterogeneity, and support the care of patients with complex syndromic disorders for whom no diagnosis is obtained through traditional clinical and genetic methods.

Challenges mentioned by Lima Jorge include the high cost of genetic tests and the fact that exome sequencing has a success rate of about 50% in diagnosing complex cases. In other words, about half of the patients undergoing such analysis still need to continue searching for a conclusive diagnosis.


São Paulo Research Foundation (FAPESP)

Journal reference:

Rezende, RC, et al. (2024). Exome sequencing identifies multiple genetic diagnoses in children with syndromic growth disorders. The Journal of Pediatrics. doi.org/10.1016/j.jpeds.2023.113841.

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